Essential roles of IL-12 and dendritic cells but not IL-23 and macrophages in lupus-like diseases initiated by cell surface HSP gp96.
Proinflammatory cytokine IL-23 but not IL-12 is critical for the pathogenesis of organ-specific autoimmune diseases including experimental autoimmune encephalitis and collagen-induced arthritis. The contribution by IL-23 in systemic autoimmune diseases such as lupus is undefined. We addressed this question in a murine lupus-like disease model, initiated by enforced cell-surface expression of an ER HSP gp96 in C57BL/6 background. We found a significant increase of p40 in the sera in these mice that preceded the onset of diseases. However, autoimmunity was abrogated in transgenic mice expressing membrane-bound gp96 reconstituted with p35-/- BM, but not with p19-/- BM. Moreover, we found that dendritic cells (DC) but not macrophages were the main producers of p40. To dissect the roles of DC further, we depleted DC using a diphtheria toxin-based inducible DC depletion system. We demonstrated that the integrity of DC was essential for autoimmunity. Our results thus revealed that IL-12 and DC are critical for the pathogenesis of lupus-like disease precipitated by cell surface gp96. This study further highlighted the significant biological differences between IL-12 and IL-23.
Dai
Jie
J
Center for Immunotherapy of Cancer and Infectious Diseases, Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06030-1601, USA.
Liu
Bei
B
Cua
Daniel J
DJ
Li
Zihai
Z
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000502:physiology*; D000954:Antigens, Surface / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000502:physiology*; D053759:Interleukin-23 / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D053759:Interleukin-23; C052646:sarcoma glycoprotein gp96 rejection antigens; D018664:Interleukin-12