Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4 + T cells

Shinichiro Sawa, Daisuke Kamimura, Gui Hua Jin, Hideyuki Morikawa, Hokuto Kamon, Mika Nishihara, Katsuhiko Ishihara, Masaaki Murakami, Toshio Hirano

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

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. JEM

Original languageEnglish
Pages (from-to)1459-1470
Number of pages12
JournalJournal of Experimental Medicine
Volume203
Issue number6
DOIs
Publication statusPublished - Jun 12 2006
Externally publishedYes

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Interleukin-6 Receptors
Interleukin-7
Arthritis
T-Lymphocytes
Interleukin-6
Cytokines
Mutation
Cytokine Receptor gp130
STAT3 Transcription Factor
Joint Diseases
Major Histocompatibility Complex
Transcriptional Activation
Autoimmune Diseases
Rheumatoid Arthritis
Lymphocytes
Antibodies

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4 + T cells. / Sawa, Shinichiro; Kamimura, Daisuke; Jin, Gui Hua; Morikawa, Hideyuki; Kamon, Hokuto; Nishihara, Mika; Ishihara, Katsuhiko; Murakami, Masaaki; Hirano, Toshio.

In: Journal of Experimental Medicine, Vol. 203, No. 6, 12.06.2006, p. 1459-1470.

Research output: Contribution to journalArticle

Sawa, Shinichiro ; Kamimura, Daisuke ; Jin, Gui Hua ; Morikawa, Hideyuki ; Kamon, Hokuto ; Nishihara, Mika ; Ishihara, Katsuhiko ; Murakami, Masaaki ; Hirano, Toshio. / Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4 + T cells. In: Journal of Experimental Medicine. 2006 ; Vol. 203, No. 6. pp. 1459-1470.
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