Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T cells.
Mice homozygous for the F759 mutation in the gp130 interleukin (IL)-6 receptor subunit have enhanced gp130-mediated signal transducer and activator of transcription (STAT)3 activation and spontaneously developed a lymphocyte-mediated rheumatoid arthritis-like joint disease. Here, we show that the development of the disease is dependent on both major histocompatibility complex (MHC) II-restricted CD4+ T cells and IL-6 family cytokines. In spite of the necessity for CD4+ T cells, the gp130 mutation was only required in nonhemtopoietic cells for the disease. The gp130 mutation resulted in enhanced production of IL-7. Conditional knockout of STAT3 in nonlymphoid cells showed that the enhancement of IL-7 production was dependent on STAT3 activation by IL-6 family cytokines. Homeostatic proliferation of CD4+ T cells was enhanced in gp130 mutant mice and acceleration of homeostatic proliferation enhanced the disease, whereas the inhibition of homeostatic proliferation suppressed the disease. Anti-IL-7 antibody treatment inhibited not only the enhanced homeostatic proliferation, but also the disease in gp130 mutant mice. Thus, our results show that autoimmune disease in gp130 mutant mice is caused by increased homeostatic proliferation of CD4+ T cells, which is due to elevated production of IL-7 by nonhematopoietic cells as a result of IL-6 family cytokine-gp130-STAT3 signaling.
Sawa
Shin-ichiro
S
Laboratory of Developmental Immunology, Graduate School of Frontier Bioscience and Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Kamimura
Daisuke
D
Jin
Gui-Hua
GH
Morikawa
Hideyuki
H
Kamon
Hokuto
H
Nishihara
Mika
M
Ishihara
Katsuhiko
K
Murakami
Masaaki
M
Hirano
Toshio
T
D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D050822:Cytokine Receptor gp130 / Q000235:genetics*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006706:Homeostasis; D006720:Homozygote; D006801:Humans; D015851:Interleukin-7 / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D050796:STAT3 Transcription Factor / Q000276:immunology*; D013934:Thymectomy
D015851:Interleukin-7; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130