Background/Purpose: We have reported that the route of immunization in proteoglycan-induced arthritis (PGIA) determines the T helper phenotype responsible for arthritis. Intraperitoneal (i.p.) immunization induces a Th1 IFN-γ dependent arthritis whereas subcutaneous (s.c.) immunization induces a Th17 IL-17 dependent arthritis.  IL-6 has been implicated in the control of leukocyte recruitment, differentiation, activation, and survival. In addition, IL-6 is involved in the differentiation of Th17 cells and in the inhibition of IFN-γ expression. In this study we examined the role of IL-6 in Th1- dependent PGIA and Th17- dependent PGIA.

Methods: Female BALB/c wild type (WT) and IL-6^-/- littermate mice (>3 months of age) were immunized i.p. or s.c. with the G1 domain of human PG in adjuvant 3 times at 3 week intervals. Paws were examined every third day for arthritis and scored based on the intensity of erythema and swelling on a scale of 1-4. For short term in vivo T cell priming, mice were immunized and cells harvested on day 9. T cells from T cell receptor (TCR) Tg mice were transferred in WT and IL-6^-/-mice and immunized with PG in adjuvant. TCR cells were recovered 5 days later.  ELISA was used to measure cytokines. Intracellular cytokines were measured by flow cytometry.

Results: In IL-6^-/- mice, the onset and severity of arthritis was significantly reduced in both i.p. and s.c immunized mice in comparison to WT. The reduction in arthritis was associated with a reduction in IL-17 in both i.p. and s.c. immunized mice but only with reduction in IFN-γ in s.c. immunized mice. To determine the role of IL-6 in early T cell cytokine production after i.p. versus s.c immunization, we assessed IFN-γ and IL-17 in CD4+ T cells on day 9 after immunization or in TCR transfer into IL-6^-/- mice.  Despite a reduction in IFN-γ levels after arthritis induction, IFN-γ was significantly increased in s.c immunized IL-6^-/-mice in comparison to i.p. immunized mice or WT mice.  IL-17 was reduced after either i.p. or s.c. immunization.

Conclusion: IL-6 is required for IL-17- and IFN-γ-dependent arthritis induced by s.c. and i.p. immunization respectively. Interestingly, despite the fact that IL-6 is known to inhibit IFN-γ, arthritis was suppressed in the IFN-γ-dependent arthritis induced by i.p. immunization.  These results suggest that IL-6 effects on arthritis may be boarder than T helper cytokine responses.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-6-is-required-for-th1-and-th17-mediated-arthritis/