The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 synergizes with HTLV-1 pX in promoting rheumatoid arthritis-like arthritis

Abstract

Rheumatoid arthritis (RA) is a polygenic autoimmune disease. The autoimmunity develops from synergistic actions of genetic and environmental factors. We generated a double-mutant mouse by crossing two murine models of RA, a gp130 mutant knock-in mouse (gp130F759/F759) and an HTLV-1 pX transgenic mouse (pX-Tg), in a C57BL/6 background, which is resistant to arthritis. The mice spontaneously developed severe arthritis with a much earlier onset than the gp130F759/F759 mice and with a much higher incidence than did the pX-Tg mice. The symptoms of gp130F759/F759 mice, including lymphoadenopathy, splenomegaly, hyper-gamma-globulinemia, autoantibody production, increases in memory/activated T cells and granulocytes in the peripheral lymphoid organs, and a decrease in the class II MHC(bright) CD11c+ population, were augmented in the double mutants. Marked reductions in incidence, severity and immunological abnormalities were seen in the triple mutant, IL-6-/-/gp130F759/F759/pX-Tg, indicating that the arthritis in the double mutant is IL-6 dependent. gp130F759/F759/pX-Tg is a unique mouse model for RA.

Interleukin-17 Promotes Autoimmunity by Triggering a Positive-Feedback Loop via Interleukin-6 Induction

“…In other words, dysregulated NF-kB activation in type I collagen + fibroblasts may trigger the feedback loop to increase IL-6 expression in F759 mice, in which IL-6-mediated STAT3 activation is already dysregulated. Consistent with this scenario, we previously showed that transgenic expression of HTLV-1-Tax, which activates NF-kB, enhanced the IL-6-dependent development of arthritis in F759 mice (Ishihara et al, 2004). Moreover, viral IL-17A from herpesvirus saimiri was shown to activate NF-kB and induce IL-6 production in fibroblasts (Yao et al, 1995).…”

“…The F759 mouse line carrying a human version of gp130 (S710L) was established previously (Atsumi et al, 2002;Ishihara et al, 2004;Sawa et al, 2006). IL-6-deficient mice were provided by M. Kopf (Max-Planck-Institute of Immunobiology, Germany), backcrossed with C57BL/6 mice more than 10 times, and crossed with F759 mice.…”

“…Mice were inspected and assessed for signs of arthritis as described previously (Atsumi et al, 2002;Ishihara et al, 2004;Sawa et al, 2006). In some experiments, knee joints were fixed in Bouin's liquid and embedded in paraffin.…”

“…The development of disease in the F759 mice is at least partially dependent on IL-6 (Sawa et al, 2006). The disease severity in the F759 mice is also accelerated in a manner dependent on IL-6 by crossing the mice with human T cell leukemia virus 1 (HTLV-1) p40-Tax transgenic mice in which nuclear factor (NF)-kB signaling was enhanced (Ishihara et al, 2004). These results suggest that IL-6 is one of critical factors for the disease in F759 mice.…”

Molecular Mechanisms of Rheumatoid Arthritis Revealed by Categorizing Subtypes of Fibroblast-Like Synoviocytes

“…Excessive activities of arthritogenic cytokines were evoked in IL-1 receptor antagonist knock-out mouse (Horai et al, 2000) lacking a physiological negative feedback molecule, and in gp130F759 with a defective, intracellular negative-regulatory signaling pathway (Atsumi et al, 2002;Ohtani et al, 2000). These wide variety of murine arthritis models with a defined genetic defect will be useful for analyzing the mechanisms for the synergistic action of genetic and environmental factors in RA development (Ishihara et al, 2004), and also the mechanisms for initiation or perpetuation of joint inflammation (Murakami et al, 2011;Ogura et al, 2008). Furthermore, bone marrow transplantation experiment revealed a unique feature of gp130F759 that nonhematopoietic cells with a point mutation Y759F in gp130 are sufficient to induce passive but arthritogenic activation of wild type CD4 + T cells (Sawa et al, 2006).…”