Chapter 11 : Biological Impact of Type I Interferon Induction Pathways beyond Their Antivirus Activity

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Biological Impact of Type I Interferon Induction Pathways beyond Their Antivirus Activity, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555815561/9781555814366_Chap11-1.gif /docserver/preview/fulltext/10.1128/9781555815561/9781555814366_Chap11-2.gif


This chapter explores three categories in which antiviral signaling, either activated by virus or active within a noninfectious context, can significantly modulate pathology. After briefly reviewing antiviral signaling, the chapter summarizes recent findings that investigate the connection between the host antiviral and antibacterial responses. It explains long-known clinical observations that viral infections can affect a patient’s susceptibility to bacteria. The chapter discusses how antiviral signaling can modulate the adaptive immune system and thereby result in enhanced or reduced, autoimmunity and inflammation. It also explores the profound metabolic consequences of the host response to viral infection and specifically elaborates how such signaling can cross talk with nuclear receptor (NR) pathways critical for metabolism of lipids and xenobiotics, leading to atherosclerosis and hepatic pathology, respectively. The interaction of the immune complexes with toll-like receptors 9 (TLR9) has been shown to promote systemic autoimmune diseases such as systemic lupus erythematosus (SLE). The chapter focuses on the role of type I interferon (IFN) in promoting and inhibiting autoimmunity. Results from one study suggested the possibility of IFN-mediated immune therapy for glomerulonephritis. It has long been known that several pathogens known as the toxoplasma, rubella, cytomegalovirus, and herpes simplex virus (TORCH) organisms can cause severe developmental defects during gestation. Importantly, in the cases of autoimmune disease it appears that the IFN system can affect the development and progress of pathology in the absence of any viral infection.

Citation: Razani B, Shahangian A, Cheng G, Guo B. 2009. Biological Impact of Type I Interferon Induction Pathways beyond Their Antivirus Activity, p 155-175. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch11
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1
Figure 1

(A) Contribution of TLR and IFN pathways to the pathogenesis of the systemic autoimmune disease SLE. (B) Role of type I IFN induction pathway in the anti-inflammatory response and in suppression of Th17-mediated, tissue-specific autoimmune diseases. (C) Cross talk between type I IFN and TGF-β in regulating mesangial cell proliferation and glomerulonephritis. IBD, inflammatory bowel disease.

Citation: Razani B, Shahangian A, Cheng G, Guo B. 2009. Biological Impact of Type I Interferon Induction Pathways beyond Their Antivirus Activity, p 155-175. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch11
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2
Figure 2

Antiviral signaling initiated by intracellular PRRs or TLR3 activation leads to an IRF3-mediated inhibition of LXR- and RXR-dependent gene transcription. Important targets of these NRs include cholesterol exporters in macrophages and aspirin-metabolizing enzymes in hepatocytes, respectively, which can enhance atherosclerosis or the aspirin-associated postviral hepatitis characteristic of Reye’s syndrome. dsRNA, double-stranded RNA.

Citation: Razani B, Shahangian A, Cheng G, Guo B. 2009. Biological Impact of Type I Interferon Induction Pathways beyond Their Antivirus Activity, p 155-175. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch11
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3
Figure 3

Outcomes of antiviral signaling initiated by PRRs or IFNAR affect host physiology in multiple ways in addition to defense against viral infection. These include modulation of antibacterial defense, adaptive immunity, and metabolic signaling.

Citation: Razani B, Shahangian A, Cheng G, Guo B. 2009. Biological Impact of Type I Interferon Induction Pathways beyond Their Antivirus Activity, p 155-175. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch11
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Adinolfi, L. E.,, M. Gambardella,, A. Andreana,, M. F. Tripodi,, R. Utili, and, G. Ruggiero. 2001. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 33: 13581364.
2. Agrawal, N.,, L. K. Chiang, and, I. R. Rifkin. 2006. Lupus nephritis. Semin. Nephrol. 26: 95104.
3. Akira, S. 2003. Toll-like receptor signaling. J. Biol. Chem. 278: 3810538108.
4. Akira, S., and, K. Takeda. 2004. Toll-like receptor signalling. Nat. Rev. Immunol. 4: 499511.
5. Akira, S.,, M. Yamamoto, and, K. Takeda. 2003. Role of adapters in Toll-like receptor signalling. Biochem. Soc. Trans. 31: 637642.
6. Alber, D. G.,, K. L. Powell,, P. Vallance,, D. A. Goodwin, and, C. Grahame-Clarke. 2000. Herpesvirus infection accelerates atherosclerosis in the apolipoprotein E-deficient mouse. Circulation 102: 779785.
7. Al-Dosari, M. S.,, J. E. Knapp, and, D. Liu. 2006. Activation of human CYP2C9 promoter and regulation by CAR and PXR in mouse liver. Mol. Pharm. 3: 322328.
8. Anders, H. J.,, B. Banas,, Y. Linde,, L. Weller,, C. D. Cohen,, M. Kretzler,, S. Martin,, V. Vielhauer,, D. Schlondorff, and, H. J. Grone. 2003. Bacterial CpG-DNA aggravates immune complex glomerulonephritis: role of TLR9-mediated expression of chemokines and chemokine receptors. J. Am. Soc. Nephrol. 14: 317326.
9. Anders, H. J., and, D. Schlondorff. 2007. Toll-like receptors: emerging concepts in kidney disease. Curr. Opin. Nephrol. Hypertens. 16: 177183.
10. Anzenbacher, P., and, E. Anzenbacherova. 2001. Cytochromes P450 and metabolism of xenobiotics. Cell. Mol. Life Sci. 58: 737747.
11. Aqel, N. M.,, R. Y. Ball,, H. Waldmann, and, M. J. Mitchinson. 1985. Identification of macrophages and smooth muscle cells in human atherosclerosis using monoclonal antibodies. J. Pathol. 146: 197204.
12. Auerbuch, V.,, D. G. Brockstedt,, N. Meyer-Morse,, M. O’Riordan, and, D. A. Portnoy. 2004. Mice lacking the type I interferon receptor are resistant to. Listeria monocytogenes. J. Exp. Med. 200: 527533.
13. Baechler, E. C.,, F. M. Batliwalla,, G. Karypis,, P. M. Gaffney,, W. A. Ortmann,, K. J. Espe,, K. B. Shark,, W. J. Grande,, K. M. Hughes,, V. Kapur,, P. K. Gregersen, and, T. W. Behrens. 2003. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc. Natl. Acad. Sci. USA 100: 26102615.
14. Barrat, F. J.,, T. Meeker,, J. H. Chan,, C. Guiducci, and, R. L. Coffman. 2007. Treatment of lupus-prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms. Eur. J. Immunol. 37: 35823586.
15. Bartalena, L.,, F. Bogazzi,, S. Brogioni,, L. Grasso, and, E. Martino. 1998. Role of cytokines in the pathogenesis of the euthyroid sick syndrome. Eur. J. Endocrinol. 138: 603614.
16. Barton, G. M., and, R. Medzhitov. 2003. Toll-like receptor signaling pathways. Science 300: 15241525.
17. Basle, M. F.,, J. G. Fournier,, S. Rozenblatt,, A. Rebel, and, M. Bouteille. 1986. Measles virus RNA detected in Paget’s disease bone tissue by in situ hybridization. J. Gen. Virol. 67(Pt. 5): 907913.
18. Basler, C. F., and, A. Garcia-Sastre. 2002. Viruses and the type I interferon antiviral system: induction and evasion. Int. Rev. Immunol. 21: 305337.
19. Beigneux, A. P.,, A. H. Moser,, J. K. Shigenaga,, C. Grunfeld, and, K. R. Feingold. 2000. The acute phase response is associated with retinoid X receptor repression in rodent liver. J. Biol. Chem. 275: 1639016399.
20. Beigneux, A. P.,, A. H. Moser,, J. K. Shigenaga,, C. Grunfeld, and, K. R. Feingold. 2003. Sick euthyroid syndrome is associated with decreased TR expression and DNA binding in mouse liver. Am. J. Physiol. Endocrinol. Metab. 284: E228E236.
21. Bekeredjian-Ding, I. B.,, M. Wagner,, V. Hornung,, T. Giese,, M. Schnurr,, S. Endres, and, G. Hartmann. 2005. Plasmacytoid dendritic cells control TLR7 sensitivity of naive B cells via type I IFN. J. Immunol. 174: 40434050.
22. Belay, E. D.,, J. S. Bresee,, R. C. Holman,, A. S. Khan,, A. Shahriari, and, L. B. Schonberger. 1999. Reye’s syndrome in the United States from 1981 through 1997. N. Engl. J. Med. 340: 13771382.
23. Bennett, L.,, A. K. Palucka,, E. Arce,, V. Cantrell,, J. Borvak,, J. Banchereau, and, V. Pascual. 2003. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197: 711723.
24. Bettelli, E.,, M. Oukka, and, V. K. Kuchroo. 2007. T H-17 cells in the circle of immunity and autoimmunity. Nat. Immunol. 8: 345350.
25. Bigler, J.,, J. Whitton,, J. W. Lampe,, L. Fosdick,, R. M. Bostick, and, J. D. Potter. 2001. CYP2C9 and UGT1A6 genotypes modulate the protective effect of aspirin on colon adenoma risk. Cancer. Res. 61: 35663569.
26. Blum, A.,, M. Giladi,, M. Weinberg,, G. Kaplan,, H. Pasternack,, S. Laniado, and, H. Miller. 1998. High anti-cytomegalovirus (CMV) IgG antibody titer is associated with coronary artery disease and may predict post-coronary balloon angioplasty restenosis. Am. J. Cardiol. 81: 866868.
27. Borden, E. C.,, G. C. Sen,, G. Uze,, R. H. Silverman,, R. M. Ransohoff,, G. R. Foster, and, G. R. Stark. 2007. Interferons at age 50: past, current and future impact on biomedicine. Nat. Rev. Drug Discov. 6: 975990.
28. Boule, M. W.,, C. Broughton,, F. Mackay,, S. Akira,, A. Marshak-Rothstein, and, I. R. Rifkin. 2004. Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes. J. Exp. Med. 199: 16311640.
29. Braun, D.,, P. Geraldes, and, J. Demengeot. 2003. Type I interferon controls the onset and severity of autoimmune manifestations in. lpr mice. J. Autoimmun. 20: 1525.
30. Breiman, A.,, N. Grandvaux,, R. Lin,, C. Ottone,, S. Akira,, M. Yoneyama,, T. Fujita,, J. Hiscott, and, E. F. Meurs. 2005. Inhibition of RIG-I-dependent signaling to the interferon pathway during hepatitis C virus expression and restoration of signaling by IKKepsilon. J. Virol. 79: 39693978.
31. Brierre, S.,, R. Kumari, and, B. P. Deboisblanc. 2004. The endocrine system during sepsis. Am. J. Med. Sci. 328: 238247.
32. Bukholm, G.,, B. P. Berdal,, C. Haug, and, M. Degre. 1984. Mouse fibroblast interferon modifies Salmonella typhimurium infection in infant mice. Infect. Immun. 45: 6266.
33. Carlin, J. M.,, E. C. Borden, and, G. I. Byrne. 1989. Interferon-induced indoleamine 2,3-dioxygenase activity inhibits Chlamydia psittaci replication in human macrophages. J. Interferon. Res. 9: 329337.
34. Carlin, J. M., and, J. B. Weller. 1995. Potentiation of interferon-mediated inhibition of Chlamydia infection by interleukin-1 in human macrophage cultures. Infect. Immun. 63: 18701875.
35. Carneiro, L. A.,, L. H. Travassos, and, S. E. Girardin. 2007. Nod-like receptors in innate immunity and inflammatory diseases. Ann. Med. 39: 581593.
36. Carrero, J. A.,, B. Calderon, and, E. R. Unanue. 2004. Type I interferon sensitizes lymphocytes to apoptosis and reduces resistance to Listeria infection. J. Exp. Med. 200: 535540.
37. Casteels-Van Daele, M.,, C. Van Geet,, C. Wouters, and, E. Eggermont. 2000. Reye syndrome revisited: a descriptive term covering a group of heterogeneous disorders. Eur. J. Pediatr. 159: 641648.
38. Casteels-Van Daele, M.,, C. Wouters,, C. Van Geet,, M. C. McGovern,, J. F. Glasgow, and, M. C. Stewart. 2002. Reye’s syndrome revisited. Outdated concept of Reye’s syndrome was used. BMJ 324: 546.
39. Castrillo, A.,, S. S. Joseph,, S. A. Vaidya,, M. Haberland,, A. M. Fogelman,, G. Cheng, and, P. Tontonoz. 2003. Crosstalk between LXR and Toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol. Cell 12: 805816.
40. Chawla, A.,, W. A. Boisvert,, C. H. Lee,, B. A. Laffitte,, Y. Barak,, S. S. Joseph,, D. Liao,, L. Nagy,, P. A. Edwards,, L. K. Curtiss,, R. M. Evans, and, P. Tontonoz. 2001. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol. Cell 7: 161171.
41. Chawla, A.,, J. J. Repa,, R. M. Evans, and, D. J. Mangelsdorf. 2001. NRs and lipid physiology: opening the X-files. Science 294: 18661870.
42. Chinetti, G.,, S. Lestavel,, V. Bocher,, A. T. Remaley,, B. Neve,, I. P. Torra,, E. Teissier,, A. Minnich,, M. Jaye,, N. Duverger,, H. B. Brewer,, J. C. Fruchart,, V. Clavey, and, B. Staels. 2001. PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat. Med. 7: 5358.
43. Chow, E. K.,, A. Castrillo,, A. Shahangian,, L. Pei,, R. M. O’Connell,, R. L. Modlin,, P. Tontonoz, and, G. Cheng. 2006. A role for IRF3-dependent RXRalpha repression in hepatotoxicity associated with viral infections. J. Exp. Med. 203: 25892602.
44. Christeff, N.,, S. Gharakhanian,, N. Thobie,, W. Rozenbaum, and, E. A. Nunez. 1992. Evidence for changes in adrenal and testicular steroids during HIV infection. J. Acquir. Immune Defic. Syndr. 5: 841846.
45. Colonna, M. 2006. Toll-like receptors and IFN-alpha: partners in autoimmunity. J. Clin. Invest. 116: 23192322.
46. Cooper, A. M.,, J. E. Pearl,, J. V. Brooks,, S. Ehlers, and, I. M. Orme. 2000. Expression of the nitric oxide synthase 2 gene is not essential for early control of Mycobacterium tuberculosis in the murine lung. Infect. Immun. 68: 68796882.
47. Cossart, P., and, M. Lecuit. 1998. Interactions of Listeria monocytogenes with mammalian cells during entry and actin-based movement: bacterial factors, cellular ligands and signaling. EMBO J. 17: 37973806.
48. Crow, M. K. 2005. Interferon pathway activation in systemic lupus erythematosus. Curr. Rheumatol Rep. 7: 463468.
49. Crow, M. K. 2007. Type I interferon in systemic lupus erythematosus. Curr. Top. Microbiol. Immunol. 316: 359386.
50. Crow, M. K.,, K. A. Kirou, and, J. Wohlgemuth. 2003. Microarray analysis of interferon-regulated genes in SLE. Autoimmunity 36: 481490.
51. Dall’era, M. C.,, P. M. Cardarelli,, B. T. Preston,, A. Witte, and, J. C. Davis, Jr. 2005. Type I interferon correlates with serological and clinical manifestations of SLE. Ann. Rheum. Dis. 64: 16921697.
52. Danesh, J.,, R. Collins, and, R. Peto. 1997. Chronic infections and coronary heart disease: is there a link? Lancet 350: 430436.
53. Danesh, J.,, P. Whincup,, M. Walker,, L. Lennon,, A. Thomson,, P. Appleby,, Y. Wong,, M. Bernardes-Silva, and, M. Ward. 2000. Chlamydia pneumoniae IgG titres and coronary heart disease: prospective study and meta-analysis. BMJ 321: 208213.
54. Davis, L. E.,, B. M. Woodfin,, T. Q. Tran,, L. S. Caskey,, J. M. Wallace,, O. U. Scremin, and, K. S. Blisard. 1993. The influenza B virus mouse model of Reye’s syndrome: pathogenesis of the hypoglycaemia. Int. J. Exp. Pathol. 74: 251258.
55. Decker, T.,, M. Muller, and, S. Stockinger. 2005. The Yin and Yang of type I interferon activity in bacterial infection. Nat. Rev. Immunol. 5: 675687.
56. Ding, C.,, L. Wang,, H. Al-Ghawi,, J. Marroquin,, M. Mamula, and, J. Yan. 2006. Toll-like receptor engagement stimulates anti-snRNP autoreactive B cells for activation. Eur. J. Immunol. 36: 20132024.
57. Doly, J.,, A. Civas,, S. Navarro, and, G. Uze. 1998. Type I interferons: expression and signalization. Cell. Mol. Life Sci. 54: 11091121.
58. Duerksen, D. R.,, L. D. Jewell,, A. L. Mason, and, V. G. Bain. 1997. Co-existence of hepatitis A and adult Reye’s syndrome. Gut 41: 121124.
59. Duez, H.,, Y. S. Chao,, M. Hernandez,, G. Torpier,, P. Poulain,, S. Mundt,, Z. Mallat,, E. Teissier,, C. A. Burton,, A. Tedgui,, J. C. Fruchart,, C. Fievet,, S. D. Wright, and, B. Staels. 2002. Reduction of atherosclerosis by the peroxi-some proliferator-activated receptor alpha agonist fenofibrate in mice. J. Biol. Chem. 277: 4805148057.
60. Dupont, I.,, F. Berthou,, P. Bodenez,, L. Bardou,, C. Guirriec,, N. Stephan,, Y. Dreano, and, D. Lucas. 1999. Involvement of cytochromes P-450 2E1 and 3A4 in the 5-hydroxylation of salicylate in humans. Drug. Metab. Dispos. 27: 322326.
61. Feingold, K.,, M. S. Kim,, J. Shigenaga,, A. Moser, and, C. Grunfeld. 2004. Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response. Am. J. Physiol. Endocrinol. Metab. 286: E201E207.
62. Ford, H., and, R. Nicholas. 2005. Multiple sclerosis. Clin. Evid. Dec: 16371651.
63. Forman, B. M.,, J. Chen, and, R. M. Evans. 1997. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc. Natl. Acad. Sci. USA 94: 43124317.
64. Freudenberg, M. A.,, T. Merlin,, C. Kalis,, Y. Chvatchko,, H. Stubig, and, C. Galanos. 2002. Cutting edge: a murine, IL-12-independent pathway of IFN-gamma induction by gram-negative bacteria based on STAT4 activation by type I IFN and IL-18 signaling. J. Immunol. 169: 16651668.
65. Furuzawa-Carballeda, J.,, M. I. Vargas-Rojas, and, A. R. Cabral. 2007. Autoimmune inflammation from the Th17 perspective. Autoimmun. Rev. 6: 169175.
66. Garcia Aparicio, A. M.,, S. Munoz Fernandez,, J. Gonzalez,, J. R. Arribas,, J. M. Pena,, J. J. Vazquez,, M. E. Martinez,, J. Coya, and, E. Martin Mola. 2006. Abnormalities in the bone mineral metabolism in HIV-infected patients. Clin. Rheumatol. 25: 537539.
67. Ghosh, D.,, D. Dhadwal,, A. Aggarwal,, S. Mitra,, S. K. Garg,, R. Kumar, and, B. Kaur. 1999. Investigation of an epidemic of Reye’s syndrome in northern region of India. Indian Pediatr. 36: 10971106.
68. Giosue, S.,, M. Casarini,, L. Alemanno,, G. Galluccio,, P. Mattia,, G. Pedicelli,, L. Rebek,, A. Bisetti, and, F. Ameglio. 1998. Effects of aerosolized interferon-alpha in patients with pulmonary tuberculosis. Am. J. Respir. Crit. Care Med. 158: 11561162.
69. Grayston, J. T.,, C. C. Kuo,, A. S. Coulson,, L. A. Campbell,, R. D. Lawrence,, M. J. Lee,, E. D. Strandness, and, S. P. Wang. 1995. Chlamydia pneumoniae (TWAR) in atherosclerosis of the carotid artery. Circulation 92: 3397400.
70. Guo, B., and, G. Cheng. 2007. Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANK. J. Biol. Chem. 282: 1181711826.
71. Gurfinkel, E.,, G. Bozovich,, A. Daroca,, E. Beck, and, B. Mautner. 1997. Randomised trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS Pilot Study. ROXIS Study Group. Lancet 350: 404407.
72. Hacker, H.,, V. Redecke,, B. Blagoev,, I. Kratchmarova,, L. C. Hsu,, G. G. Wang,, M. P. Kamps,, E. Raz,, H. Wagner,, G. Hacker,, M. Mann, and, M. Karin. 2006. Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439: 204207.
73. Haller, O.,, G. Kochs, and, F. Weber. 2007. Interferon, Mx, and viral countermeasures. Cytokine Growth Factor Rev. 18: 425433.
74. Hansson, G. K. 2005. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 352: 16851695.
75. Harrington, L. E.,, R. D. Hatton,, P. R. Mangan,, H. Turner,, T. L. Murphy,, K. M. Murphy, and, C. T. Weaver. 2005. Interleukin 17-producing CD4 + effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6: 11231132.
76. Hasegawa, K., and, T. Hayashi. 2003. Synthetic CpG oligodeoxynucleotides accelerate the development of lupus nephritis during preactive phase in NZB x NZWF1 mice. Lupus 12: 838845.
77. He, B.,, X. Qiao, and, A. Cerutti. 2004. CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10. J. Immunol. 173: 44794491.
78. Heim, M. H. 2005. RIG-I: an essential regulator of virus-induced interferon production. J. Hepatol. 42: 431433.
79. Hertzog, P. J.,, L. A. O’Neill, and, J. A. Hamilton. 2003. The interferon in TLR signaling: more than just antiviral. Trends Immunol. 24: 534539.
80. Hiscott, J.,, R. Lin,, P. Nakhaei, and, S. Paz. 2006. MasterCARD: a priceless link to innate immunity. Trends Mol. Med. 12: 5356.
81. Honda, K.,, Y. Ohba,, H. Yanai,, H. Negishi,, T. Mizutani,, A. Takaoka,, C. Taya, and, T. Taniguchi. 2005. Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434: 10351040.
82. Hornung, V.,, J. Ellegast,, S. Kim,, K. Brzozka,, A. Jung,, H. Kato,, H. Poeck,, S. Akira,, K. K. Conzelmann,, M. Schlee,, S. Endres, and, G. Hartmann. 2006. 5′-Triphosphate RNA is the ligand for RIG-I. Science 314: 994997.
83. Hourigan, L. F.,, G. A. Macdonald,, D. Purdie,, V. H. Whitehall,, C. Shorthouse,, A. Clouston, and, E. E. Powell. 1999. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 29: 12151219.
84. Howard, M.,, T. Muchamuel,, S. Andrade, and, S. Menon. 1993. Interleukin 10 protects mice from lethal endotoxemia. J. Exp. Med. 177: 12051208.
85. Huang, J.,, T. Liu,, L. G. Xu,, D. Chen,, Z. Zhai, and, H. B. Shu. 2005. SIKE is an IKKepsilon/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways. EMBO J. 24: 40184028.
86. Hurwitz, E. S.,, M. J. Barrett,, D. Bregman,, W. J. Gunn,, P. Pinsky,, L. B. Schonberger,, J. S. Drage,, R. A. Kaslow,, D. B. Burlington,, G. V. Quinnan, et al. 1987. Public Health Service study of Reye’s syndrome and medications. Report of the main study. JAMA 257: 19051911.
87. Janeway, C. A., Jr., and, R. Medzhitov. 2002. Innate immune recognition. Annu. Rev. Immunol. 20: 197216.
88. Janowski, B. A.,, P. J. Willy,, T. R. Devi,, J. R. Falck, and, D. J. Mangelsdorf. 1996. An oxysterol signalling pathway mediated by the NR LXR alpha. Nature 383: 728731.
89. Jefferies, C. A., and, K. A. Fitzgerald. 2005. Interferon gene regulation: not all roads lead to Tolls. Trends Mol. Med. 11: 403411.
90. Jiang, C.,, A. T. Ting, and, B. Seed. 1998. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 391: 8286.
91. Johnson, C. L., and, M. Gale, Jr. 2006. CARD games between virus and host get a new player. Trends Immunol. 27: 14.
92. Joseph, S. B.,, A. Castrillo,, B. A. Laffitte,, D. J. Mangelsdorf, and, P. Tontonoz. 2003. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat. Med. 9: 213219.
93. Joseph, S. B.,, E. McKilligin,, L. Pei,, M. A. Watson,, A. R. Collins,, B. A. Laffitte,, M. Chen,, G. Noh,, J. Goodman,, G. N. Hagger,, J. Tran,, T. K. Tippin,, X. Wang,, A. J. Lusis,, W. A. Hsueh,, R. E. Law,, J. L. Collins,, T. M. Willson, and, P. Tontonoz. 2002. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc. Natl. Acad. Sci. USA 99: 76047609.
94. Kaisho, T., and, S. Akira. 2006. Toll-like receptor function and signaling. J. Allergy. Clin. Immunol. 117: 979987; quiz 988.
95. Kanneganti, T. D.,, M. Lamkanfi, and, G. Nunez. 2007. Intracellular NOD-like receptors in host defense and disease. Immunity 27: 549559.
96. Karaghiosoff, M.,, R. Steinborn,, P. Kovarik,, G. Kriegshauser,, M. Baccarini,, B. Donabauer,, U. Reichart,, T. Kolbe,, C. Bogdan,, T. Leanderson,, D. Levy,, T. Decker, and, M. Muller. 2003. Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock. Nat. Immunol. 4: 471477.
97. Kato, H.,, S. Sato,, M. Yoneyama,, M. Yamamoto,, S. Uematsu,, K. Matsui,, T. Tsujimura,, K. Takeda,, T. Fujita,, O. Takeuchi, and, S. Akira. 2005. Cell type-specific involvement of RIG-I in antiviral response. Immunity 23: 1928.
98. Kato, H.,, O. Takeuchi,, S. Sato,, M. Yoneyama,, M. Yamamoto,, K. Matsui,, S. Uematsu,, A. Jung,, T. Kawai,, K. J. Ishii,, O. Yamaguchi,, K. Otsu,, T. Tsujimura,, C. S. Koh,, C. Reis e Sousa,, Y. Matsuura,, T. Fujita, and, S. Akira. 2006. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441: 101105.
99. Kawai, T., and, S. Akira. 2006. TLR signaling. Cell Death Differ. 13: 816825.
100. Kawai, T.,, K. Takahashi,, S. Sato,, C. Coban,, H. Kumar,, H. Kato,, K. J. Ishii,, O. Takeuchi, and, S. Akira. 2005. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol. 6: 981988.
101. Kim, M. S.,, J. Shigenaga,, A. Moser,, K. Feingold, and, C. Grunfeld. 2003. Repression of farnesoid X receptor during the acute phase response. J. Biol. Chem. 278: 89888995.
102. Kliewer, S. A.,, S. S. Sundseth,, S. A. Jones,, P. J. Brown,, G. B. Wisely,, C. S. Koble,, P. Devchand,, W. Wahli,, T. M. Willson,, J. M. Lenhard, and, J. M. Lehmann. 1997. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc. Natl. Acad. Sci. USA 94: 43184323.
103. Komiyama, Y.,, S. Nakae,, T. Matsuki,, A. Nambu,, H. Ishigame,, S. Kakuta,, K. Sudo, and, Y. Iwakura. 2006. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177: 566573.
104. Kono, D. H.,, R. Baccala, and, A. N. Theofilopoulos. 2003. Inhibition of lupus by genetic alteration of the interferon-alpha/beta receptor. Autoimmunity 36: 503510.
105. Korn, T.,, M. Oukka,, V. Kuchroo, and, E. Bettelli. 2007. Th17 cells: effector T cells with inflammatory properties. Semin Immunol. 19: 362371.
106. Kramer, J. M., and, S. L. Gaffen. 2007. Interleukin-17: a new paradigm in inflammation, autoimmunity, and therapy. J. Periodontol. 78: 10831093.
107. Krug, A.,, A. R. French,, W. Barchet,, J. A. Fischer,, A. Dzionek,, J. T. Pingel,, M. M. Orihuela,, S. Akira,, W. M. Yokoyama, and, M. Colonna. 2004. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 21: 107119.
108. Kuehl, G. E.,, J. Bigler,, J. D. Potter, and, J. W. Lampe. 2006. Glucuronidation of the aspirin metabolite salicylic acid by expressed UDP-glucuronosyltransferases and human liver microsomes. Drug Metab. Dispos. 34: 199202.
109. Kumar, H.,, T. Kawai,, H. Kato,, S. Sato,, K. Takahashi,, C. Coban,, M. Yamamoto,, S. Uematsu,, K. J. Ishii,, O. Takeuchi, and, S. Akira. 2006. Essential role of IPS-1 in innate immune responses against RNA viruses. J. Exp. Med. 203: 17951803.
110. Lau, C. M.,, C. Broughton,, A. S. Tabor,, S. Akira,, R. A. Flavell,, M. J. Mamula,, S. R. Christensen,, M. J. Shlomchik,, G. A. Viglianti,, I. R. Rifkin, and, A. MarshakRothstein. 2005. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202: 11711177.
111. Leadbetter, E. A.,, I. R. Rifkin,, A. M. Hohlbaum,, B. C. Beaudette,, M. J. Shlomchik, and, A. Marshak-Rothstein. 2002. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416: 603607.
112. Le Bon, A.,, G. Schiavoni,, G. D’Agostino,, I. Gresser,, F. Belardelli, and, D. F. Tough. 2001. Type I interferons potently enhance humoral immunity and can promote iso-type switching by stimulating dendritic cells in vivo. Immunity 14: 461470.
113. Le Bon, A.,, C. Thompson,, E. Kamphuis,, V. Durand,, C. Rossmann,, U. Kalinke, and, D. F. Tough. 2006. Cutting edge: enhancement of antibody responses through direct stimulation of B and T cells by type I IFN. J. Immunol. 176: 20742078.
114. Lee, C. H.,, A. Chawla,, N. Urbiztondo,, D. Liao,, W. A. Boisvert,, R. M. Evans, and, L. K. Curtiss. 2003. Transcriptional repression of atherogenic inflammation: modulation by PPARdelta. Science 302: 453457.
115. Lee, C. K.,, D. T. Rao,, R. Gertner,, R. Gimeno,, A. B. Frey, and, D. E. Levy. 2000. Distinct requirements for IFNs and Stat1 in NK cell function. J. Immunol. 165: 35713577.
116. Lee, M. S., and, Y. J. Kim. 2007. Pattern-recognition receptor signaling initiated from extracellular, membrane, and cytoplasmic space. Mol. Cells 23: 110.
117. Lehmann, J. M.,, S. A. Kliewer,, L. B. Moore,, T. A. Smith-Oliver,, B. B. Oliver,, J. L. Su,, S. S. Sundseth,, D. A. Winegar,, D. E. Blanchard,, T. A. Spencer, and, T. M. Willson. 1997. Activation of the NR LXR by oxysterols defines a new hormone response pathway. J. Biol. Chem. 272: 31373140.
118. Lehmann, J. M.,, D. D. McKee,, M. A. Watson,, T. M. Willson,, J. T. Moore, and, S. A. Kliewer. 1998. The human orphan NR PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Invest. 102: 10161023.
119. Lenert, P.,, R. Brummel,, E. H. Field, and, R. F. Ashman. 2005. TLR-9 activation of marginal zone B cells in lupus mice regulates immunity through increased IL-10 production. J. Clin. Immunol. 25: 2940.
120. Le Page, C.,, P. Genin,, M. G. Baines, and, J. Hiscott. 2000. Interferon activation and innate immunity. Rev. Immunogenet. 2: 374386.
121. Levy, D. E., and, A. Garcia-Sastre. 2001. The virus battles: IFN induction of the antiviral state and mechanisms of viral evasion. Cytokine Growth Factor Rev. 12: 143156.
122. Li, A. C.,, K. K. Brown,, M. J. Silvestre,, T. M. Willson,, W. Palinski, and, C. K. Glass. 2000. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J. Clin. Invest. 106: 523531.
123. Li, A. C., and, W. Palinski. 2006. Peroxisome proliferator-activated receptors: how their effects on macrophages can lead to the development of a new drug therapy against atherosclerosis. Annu. Rev. Pharmacol. Toxicol. 46: 139.
124. Loo, Y. M.,, J. Fornek,, N. Crochet,, G. Bajwa,, O. Perwitasari,, L. Martinez-Sobrido,, S. Akira,, M. A. Gill,, A. Garcia-Sastre,, M. G. Katze, and, M. Gale, Jr. 2008. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J. Virol. 82: 335345.
125. Loo, Y. M., and, M. Gale, Jr. 2007. Viral regulation and evasion of the host response. Curr. Top. Microbiol. Immunol. 316: 295313.
126. Manca, C.,, L. Tsenova,, A. Bergtold,, S. Freeman,, M. Tovey,, J. M. Musser,, C. E. Barry III,, V. H. Freedman, and, G. Kaplan. 2001. Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-alpha/beta. Proc. Natl. Acad. Sci. USA 98: 57525757.
127. Mancuso, G.,, A. Midiri,, C. Biondo,, C. Beninati,, S. Zummo,, R. Galbo,, F. Tomasello,, M. Gambuzza,, G. Macri,, A. Ruggeri,, T. Leanderson, and, G. Teti. 2007. Type I IFN signaling is crucial for host resistance against different species of pathogenic bacteria. J. Immunol. 178: 31263133.
128. Manganelli, P.,, N. Giuliani,, P. Fietta,, C. Mancini,, M. Lazzaretti,, A. Pollini,, F. Quaini, and, M. Pedrazzoni. 2005. OPG/RANKL system imbalance in a case of hepatitis C-associated osteosclerosis: the pathogenetic key? Clin. Rheumatol. 24: 296300.
129. Marrack, P.,, J. Kappler, and, T. Mitchell. 1999. Type I interferons keep activated T cells alive. J. Exp. Med. 189: 521530.
130. Marshak-Rothstein, A. 2006. Toll-like receptors in systemic autoimmune disease. Nat. Rev. Immunol. 6: 823835.
131. Martens, M. E.,, C. H. Chang, and, C. P. Lee. 1986. Reye’s syndrome: mitochondrial swelling and Ca 2+ release induced by Reye’s plasma, allantoin, and salicylate. Arch. Biochem. Biophys. 244: 773786.
132. Means, T. K.,, E. Latz,, F. Hayashi,, M. R. Murali,, D. T. Golenbock, and, A. D. Luster. 2005. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Invest. 115: 407417.
133. Melnick, J. L.,, C. Hu,, J. Burek,, E. Adam, and, M. E. DeBakey. 1994. Cytomegalovirus DNA in arterial walls of patients with atherosclerosis. J. Med. Virol. 42: 170174.
134. Melnick, J. L.,, B. L. Petrie,, G. R. Dreesman,, J. Burek,, C. H. McCollum, and, M. E. DeBakey. 1983. Cytomegalovirus antigen within human arterial smooth muscle cells. Lancet 2: 644647.
135. Meylan, E.,, J. Curran,, K. Hofmann,, D. Moradpour,, M. Binder,, R. Bartenschlager, and, J. Tschopp. 2005. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437: 11671172.
136. Michitaka, K.,, N. Horiike,, Y. Chen,, T. N. Duong,, I. Konishi,, T. Mashiba,, Y. Tokumoto,, Y. Hiasa,, Y. Tanaka,, M. Mizokami, and, M. Onji. 2004. Gianotti-Crosti syndrome caused by acute hepatitis B virus genotype D infection. Intern. Med. 43: 696699.
137. Muhlestein, J. B.,, J. L. Anderson,, J. F. Carlquist,, K. Salunkhe,, B. D. Horne,, R. R. Pearson,, T. J. Bunch,, A. Allen,, S. Trehan, and, C. Nielson. 2000. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease: primary clinical results of the ACADEMIC study. Circulation 102: 17551760.
138. Muhlestein, J. B.,, J. L. Anderson,, E. H. Hammond,, L. Zhao,, S. Trehan,, E. P. Schwobe, and, J. F. Carlquist. 1998. Infection witH Chlamydia pneumoniae accelerates the development of atherosclerosis and treatment with azithromycin prevents it in a rabbit model. Circulation 97: 633636.
139. Munro, J. M.,, J. D. van der Walt,, C. S. Munro,, J. A. Chalmers, and, E. L. Cox. 1987. An immunohistochemical analysis of human aortic fatty streaks. Hum. Pathol. 18: 375380.
140. Nacionales, D. C.,, K. M. Kelly-Scumpia,, P. Y. Lee,, J. S. Weinstein,, R. Lyons,, E. Sobel,, M. Satoh, and, W. H. Reeves. 2007. Deficiency of the type I interferon receptor protects mice from experimental lupus. Arthritis Rheum. 56: 37703783.
141. Nagpal, S.,, J. Lu, and, M. F. Boehm. 2001. Vitamin D analogs: mechanism of action and therapeutic applications. Curr. Med. Chem. 8: 16611679.
142. Niemir, Z. I.,, H. Stein,, I. L. Noronha,, C. Kruger,, K. Andrassy,, E. Ritz, and, R. Waldherr. 1995. PDGF and TGF-beta contribute to the natural course of human IgA glomerulonephritis. Kidney Int. 48: 15301541.
143. Niesel, D. W.,, C. B. Hess,, Y. J. Cho,, K. D. Klimpel, and, G. R. Klimpel. 1986. Natural and recombinant interferons inhibit epithelial cell invasion by Shigella spp. Infect. Immun. 52: 828833.
144. Nieto, F. J.,, E. Adam,, P. Sorlie,, H. Farzadegan,, J. L. Melnick,, G. W. Comstock, and, M. Szklo. 1996. Cohort study of cytomegalovirus infection as a risk factor for carotid intimal-medial thickening, a measure of subclinical atherosclerosis. Circulation 94: 922927.
145. Norman, A. W. 2006. Minireview: vitamin D receptor: new assignments for an already busy receptor. Endocrinology 147: 55425548.
146. Nurieva, R.,, X. O. Yang,, G. Martinez,, Y. Zhang,, A. D. Panopoulos,, L. Ma,, K. Schluns,, Q. Tian,, S. S. Watowich,, A. M. Jetten, and, C. Dong. 2007. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448: 480483.
147. O’ Connell, R. M.,, S. K. Saha,, S. A. Vaidya,, K. W. Bruhn,, G. A. Miranda,, B. Zarnegar,, A. K. Perry,, B. O. Nguyen,, T. F. Lane,, T. Taniguchi,, J. F. Miller, and, G. Cheng. 2004. Type I interferon production enhances susceptibility to Listeria monocytogenes infection. J. Exp. Med. 200: 437445.
148. Oganesyan, G.,, S. K. Saha,, B. Guo,, J. Q. He,, A. Shahangian,, B. Zarnegar,, A. Perry, and, G. Cheng. 2006. Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 439: 208211.
149. Oganesyan, G.,, S. K. Saha,, E. M. Pietras,, B. Guo,, A. K. Miyahira,, B. Zarnegar, and, G. Cheng. 2007. IRF3-dependent type I interferon response in B cells regulates CpG-mediated antibody production. J. Biol. Chem. 283: 802808.
150. Ogasawara, K.,, S. Hida,, Y. Weng,, A. Saiura,, K. Sato,, H. Takayanagi,, S. Sakaguchi,, T. Yokochi,, T. Kodama,, M. Naitoh,, J. A. De Martino, and, T. Taniguchi. 2002. Requirement of the IFN-alpha/beta-induced CXCR3 chemokine signalling for CD8 + T cell activation. Genes Cells 7: 309320.
151. Onomoto, K.,, M. Yoneyama, and, T. Fujita. 2007. Regulation of antiviral innate immune responses by RIG-I family of RNA helicases. Curr. Top. Microbiol. Immunol. 316: 193205.
152. Opitz, B.,, M. Vinzing,, V. van Laak,, B. Schmeck,, G. Heine,, S. Gunther,, R. Preissner,, H. Slevogt,, P. D. N’Guessan,, J. Eitel,, T. Goldmann,, A. Flieger,, N. Suttorp, and, S. Hippenstiel. 2006. Legionella pneumophila induces IFNbeta in lung epithelial cells via IPS-1 and IRF3, which also control bacterial replication. J. Biol. Chem. 281: 3617336179.
153. Orlowski, J. P.,, P. Campbell, and, S. Goldstein. 1990. Reye’s syndrome: a case control study of medication use and associated viruses in Australia. Cleve. Clin. J. Med. 57: 323329.
154. Park, H.,, Z. Li,, X. O. Yang,, S. H. Chang,, R. Nurieva,, Y. H. Wang,, Y. Wang,, L. Hood,, Z. Zhu,, Q. Tian, and, C. Dong. 2005. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6: 11331141.
155. Partin, J. C.,, W. K. Schubert, and, J. S. Partin. 1971. Mitochondrial ultrastructure in Reye’s syndrome (encephalopathy and fatty degeneration of the viscera). N. Engl. J. Med. 285: 13391343.
156. Pascual, G., and, C. K. Glass. 2006. NRs versus inflammation: mechanisms of transrepression. Trends Endocrinol. Metab. 17: 321327.
157. Pascual, V.,, L. Farkas, and, J. Banchereau. 2006. Systemic lupus erythematosus: all roads lead to type I interferons. Curr. Opin. Immunol. 18: 676682.
158. Patton, H. M.,, K. Patel,, C. Behling,, D. Bylund,, L. M. Blatt,, M. Vallee,, S. Heaton,, A. Conrad,, P. J. Pockros, and, J. G. McHutchison. 2004. The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J. Hepatol. 40: 484490.
159. Paul, S.,, C. Ricour,, C. Sommereyns,, F. Sorgeloos, and, T. Michiels. 2007. Type I interferon response in the central nervous system. Biochimie 89: 770778.
160. Perry, A. K.,, G. Chen,, D. Zheng,, H. Tang, and, G. Cheng. 2005. The host type I interferon response to viral and bacterial infections. Cell Res. 15: 407422.
161. Petrilli, V.,, C. Dostert,, D. A. Muruve, and, J. Tschopp. 2007. The inflammasome: a danger sensing complex triggering innate immunity. Curr. Opin. Immunol. 19: 615622.
162. Pitha, P. M., and, M. S. Kunzi. 2007. Type I interferon: the ever unfolding story. Curr. Top. Microbiol. Immunol. 316: 4170.
163. Poeck, H.,, M. Wagner,, J. Battiany,, S. Rothenfusser,, D. Wellisch,, V. Hornung,, B. Jahrsdorfer,, T. Giese,, S. Endres, and, G. Hartmann. 2004. Plasmacytoid dendritic cells, antigen, and CpG-C license human B cells for plasma cell differentiation and immunoglobulin production in the absence of T-cell help. Blood 103: 30583064.
164. Ratziu, V.,, A. Heurtier,, L. Bonyhay,, T. Poynard, and, P. Giral. 2005. Review article: an unexpected virus-host interaction—the hepatitis C virus-diabetes link. Aliment. Pharmacol. Ther. 22 (Suppl. 2): 5660.
165. Rebel, A.,, M. Basle,, A. Pouplard,, K. Malkani,, R. Filmon, and, A. Lepatezour. 1981. Towards a viral etiology for Paget’s disease of bone. Metab. Bone. Dis. Relat. Res. 3: 235238.
166. Renaudineau, Y.,, J. O. Pers,, B. Bendaoud,, C. Jamin, and, P. Youinou. 2004. Dysfunctional B cells in systemic lupus erythematosus. Autoimmun. Rev. 3: 516523.
167. Repa, J. J.,, K. E. Berge,, C. Pomajzl,, J. A. Richardson,, H. Hobbs, and, D. J. Mangelsdorf. 2002. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J. Biol. Chem. 277: 1879318800.
168. Ribeiro, R. C.,, P. J. Kushner, and, J. D. Baxter. 1995. The nuclear hormone receptor gene superfamily. Annu. Rev. Med. 46: 443453.
169. Ricote, M.,, A. C. Li,, T. M. Willson,, C. J. Kelly, and, C. K. Glass. 1998. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391: 7982.
170. Rifkin, I. R.,, E. A. Leadbetter,, B. C. Beaudette,, C. Kiani,, M. Monestier,, M. J. Shlomchik, and, A. MarshakRothstein. 2000. Immune complexes present in the sera of autoimmune mice activate rheumatoid factor B cells. J. Immunol. 165: 16261633.
171. Rifkin, I. R.,, E. A. Leadbetter,, L. Busconi,, G. Viglianti, and, A. Marshak-Rothstein. 2005. Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol. Rev. 204: 2742.
172. Ronnblom, L.,, M. L. Eloranta, and, G. V. Alm. 2003. Role of natural interferon-alpha producing cells (plasma-cytoid dendritic cells) in autoimmunity. Autoimmunity 36: 463472.
173. Rosenstiel, P.,, A. Till, and, S. Schreiber. 2007. NOD-like receptors and human diseases. Microbes Infect. 9: 648657.
174. Sadlier, D. M.,, X. Ouyang,, B. McMahon,, W. Mu,, R. Ohashi,, K. Rodgers,, D. Murray,, T. Nakagawa,, C. Godson,, P. Doran,, H. R. Brady, and, R. J. Johnson. 2005. Microarray and bioinformatic detection of novel and established genes expressed in experimental anti-Thy1 nephritis. Kidney Int. 68: 25422561.
175. Saha, S. K.,, E. M. Pietras,, J. Q. He,, J. R. Kang,, S. Y. Liu,, G. Oganesyan,, A. Shahangian,, B. Zarnegar,, T. L. Shiba,, Y. Wang, and, G. Cheng. 2006. Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif. EMBO J. 25: 32573263.
176. Saikku, P.,, M. Leinonen,, K. Mattila,, M. R. Ekman,, M. S. Nieminen,, P. H. Makela,, J. K. Huttunen, and, V. Valtonen. 1988. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 2: 983986.
177. Sakaguchi, S.,, H. Negishi,, M. Asagiri,, C. Nakajima,, T. Mizutani,, A. Takaoka,, K. Honda, and, T. Taniguchi. 2003. Essential role of IRF-3 in lipopolysaccharide-induced interferon-β gene expression and endotoxin shock. Biochem. Biophys. Res. Commun. 306: 860866.
178. Santiago-Raber, M. L.,, R. Baccala,, K. M. Haraldsson,, D. Choubey,, T. A. Stewart,, D. H. Kono, and, A. N. Theofilopoulos. 2003. Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J. Exp. Med. 197: 777788.
179. Schaefer, C.,, T. R. Hidalgo,, L. Cashion,, H. Petry,, A. Brooks,, P. Szymanski,, H. S. Qian,, C. Gross,, P. Wang,, P. Liu,, C. Goldman,, G. M. Rubanyi, and, R. N. Harkins. 2006. Gene-based delivery of IFN-beta is efficacious in a murine model of experimental allergic encephalomyelitis. J. Interferon Cytokine Res. 26: 449454.
180. Scheuer, P. J.,, P. Ashrafzadeh,, S. Sherlock,, D. Brown, and, G. M. Dusheiko. 1992. The pathology of hepatitis C. Hepatology 15: 567571.
181. Schiavoni, G.,, C. Mauri,, D. Carlei,, F. Belardelli,, M. Castellani Pastoris, and, E. Proietti. 2004. Type I IFN protects permissive macrophages from Legionella pneumophila infection through an IFN-γ-independent pathway. J. Immunol. 173: 12661275.
182. Schneider, K.,, C. A. Benedict, and, C. F. Ware. 2006. A TRAFfic cop for host defense. Nat. Immunol. 7: 1516.
183. Sen, G. C., and, G. A. Peters. 2007. Viral stress-inducible genes. Adv. Virus Res. 70: 233263.
184. Seth, R. B.,, L. Sun, and, Z. J. Chen. 2006. Antiviral innate immunity pathways. Cell Res. 16: 141147.
185. Seth, R. B.,, L. Sun,, C. K. Ea, and, Z. J. Chen. 2005. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NFkappaB and IRF 3. Cell 122: 669682.
186. Shemer-Avni, Y.,, D. Wallach, and, I. Sarov. 1989. Reversion of the antichlamydial effect of tumor necrosis factor by tryptophan and antibodies to beta interferon. Infect. Immun. 57: 34843490.
187. Shi, Y., and, O. Tokunaga. 2002. Chlamydia pneumoniae and multiple infections in the aorta contribute to atherosclerosis. Pathol. Int. 52: 755763.
188. Smoak, K. A., and, J. A. Cidlowski. 2004. Mechanisms of glucocorticoid receptor signaling during inflammation. Mech. Ageing Dev. 125: 697706.
189. Stegmann, B. J., and, J. C. Carey. 2002. TORCH Infections. Toxoplasmosis, other (syphilis, varicella-zoster, parvovirus B19), rubella, cytomegalovirus (CMV), and herpes infections. Curr. Womens Health Rep. 2: 253258.
190. Steinman, L. 2007. A brief history of T H17, the first major revision in the T H1/T H2 hypothesis of T cell-mediated tissue damage. Nat. Med. 13: 139145.
191. Stetson, D. B., and, R. Medzhitov. 2006. Antiviral defense: interferons and beyond. J. Exp. Med. 203: 18371841.
192. Stetson, D. B., and, R. Medzhitov. 2006. Type I interferons in host defense. Immunity 25: 373381.
193. Stockinger, B., and, M. Veldhoen. 2007. Differentiation and function of Th17 T cells. Curr. Opin. Immunol. 19: 281286.
194. Strober, W.,, I. J. Fuss, and, R. S. Blumberg. 2002. The immunology of mucosal models of inflammation. Annu. Rev. Immunol. 20: 495549.
195. Takaoka, A.,, Z. Wang,, M. K. Choi,, H. Yanai,, H. Negishi,, T. Ban,, Y. Lu,, M. Miyagishi,, T. Kodama,, K. Honda,, Y. Ohba, and, T. Taniguchi. 2007. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448: 501505.
196. Takeda, K., and, S. Akira. 2005. Toll-like receptors in innate immunity. Int. Immunol. 17: 114.
197. Takeuchi, O.,, H. Hemmi, and, S. Akira. 2004. Interferon response induced by Toll-like receptor signaling. J. Endotoxin Res. 10: 252256.
198. Tangirala, R. K.,, E. D. Bischoff,, S. B. Joseph,, B. L. Wagner,, R. Walczak,, B. A. Laffitte,, C. L. Daige,, D. Thomas,, R. A. Heyman,, D. J. Mangelsdorf,, X. Wang,, A. J. Lusis,, P. Tontonoz, and, I. G. Schulman. 2002. Identification of macrophage liver X receptors as inhibitors of atherosclerosis. Proc. Natl. Acad. Sci. USA 99: 1189611901.
199. Taniguchi, T., and, A. Takaoka. 2002. The interferonalpha/beta system in antiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors. Curr. Opin. Immunol. 14: 111116.
200. Teige, I.,, A. Treschow,, A. Teige,, R. Mattsson,, V. Navikas,, T. Leanderson,, R. Holmdahl, and, S. Issazadeh-Navikas. 2003. IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis. J. Immunol. 170: 47764784.
201. Theofilopoulos, A. N.,, R. Baccala,, B. Beutler, and, D. H. Kono. 2005. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu. Rev. Immunol. 23: 307336.
202. Tordjman, K.,, C. Bernal-Mizrachi,, L. Zemany,, S. Weng,, C. Feng,, F. Zhang,, T. C. Leone,, T. Coleman,, D. P. Kelly, and, C. F. Semenkovich. 2001. PPARalpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice. J. Clin. Invest. 107: 10251034.
203. Tough, D. F.,, P. Borrow, and, J. Sprent. 1996. Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 272: 19471950.
204. Tourbah, A., and, O. Lyon-Caen. 2007. Interferons in multiple sclerosis: ten years’ experience. Biochimie 89: 899902.
205. Trost, L. C., and, J. J. Lemasters. 1997. Role of the mitochondrial permeability transition in salicylate toxicity to cultured rat hepatocytes: implications for the pathogenesis of Reye’s syndrome. Toxicol. Appl. Pharmacol. 147: 431441.
206. Venkateswaran, A.,, B. A. Laffitte,, S. B. Joseph,, P. A. Mak,, D. C. Wilpitz,, P. A. Edwards, and, P. Tontonoz. 2000. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc. Natl. Acad. Sci. USA 97: 1209712102.
207. Venkateswaran, A.,, J. J. Repa,, J. M. Lobaccaro,, A. Bronson,, D. J. Mangelsdorf, and, P. A. Edwards. 2000. Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols. J. Biol. Chem. 275: 1470014707.
208. Vliegen, I.,, S. B. Herngreen,, G. E. Grauls,, C. A. Bruggeman, and, F. R. Stassen. 2005. Mouse cytomegalovirus antigenic immune stimulation is sufficient to aggravate atherosclerosis in hypercholesterolemic mice. Atherosclerosis 181: 3944.
209. Wada, J.,, H. Sugiyama, and, H. Makino. 2003. Pathogenesis of IgA nephropathy. Semin. Nephrol. 23: 556563.
210. Weigent, D. A.,, T. L. Huff,, J. W. Peterson,, G. J. Stanton, and, S. Baron. 1986. Role of interferon in streptococcal infection in the mouse. Microb. Pathog. 1: 399407.
211. Xie, W.,, A. Radominska-Pandya,, Y. Shi,, C. M. Simon,, M. C. Nelson,, E. S. Ong,, D. J. Waxman, and, R. M. Evans. 2001. An essential role for NRs SXR/PXR in detoxification of choleStatic bile acids. Proc. Natl. Acad. Sci. USA 98: 33753380.
212. Xu, L. G.,, Y. Y. Wang,, K. J. Han,, L. Y. Li,, Z. Zhai, and, H. B. Shu. 2005. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol. Cell. 19: 727740.
213. Yoneyama, H.,, K. Matsuno,, E. Toda,, T. Nishiwaki,, N. Matsuo,, A. Nakano,, S. Narumi,, B. Lu,, C. Gerard,, S. Ishikawa, and, K. Matsushima. 2005. Plasmacytoid DCs help lymph node DCs to induce anti-HSV CTLs. J. Exp. Med. 202: 425435.
214. Yoneyama, M., and, T. Fujita. 2007. Function of RIG-I-like receptors in antiviral innate immunity. J. Biol. Chem. 282: 1531515318.
215. Yoneyama, M., and, T. Fujita. 2007. RIG-I family RNA helicases: cytoplasmic sensor for antiviral innate immunity. Cytokine Growth Factor Rev. 18: 545551.
216. Yoneyama, M.,, M. Kikuchi,, T. Natsukawa,, N. Shinobu,, T. Imaizumi,, M. Miyagishi,, K. Taira,, S. Akira, and, T. Fujita. 2004. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5: 730737.
217. Zelcer, N., and, P. Tontonoz. 2006. Liver X receptors as integrators of metabolic and inflammatory signaling. J. Clin. Invest. 116: 607614.
218. Zheng, S. J.,, J. Jiang,, H. Shen, and, Y. H. Chen. 2004. Reduced apoptosis and ameliorated listeriosis in TRAIL-null mice. J. Immunol. 173: 56525658.
219. Zile, M. H. 2001. Function of vitamin A in vertebrate embryonic development. J. Nutr. 131: 705708.
220. Zuniga, E. I.,, B. Hahm, and, M. B. Oldstone. 2007. Type I interferon during viral infections: multiple triggers for a multifunctional mediator. Curr. Top. Microbiol. Immunol. 316: 337357.


Generic image for table
Table 1

Effects of type I interferons on host response to bacterial infection

Citation: Razani B, Shahangian A, Cheng G, Guo B. 2009. Biological Impact of Type I Interferon Induction Pathways beyond Their Antivirus Activity, p 155-175. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch11

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error