Defective regulation of IFNγ and IL-12 by endogenous IL-10 in progressive MS

Abstract

Background: MS is a chronic inflammatory disease of the CNS postulated to be a Th1 type cell–mediated autoimmune disease. There is increased interferon-γ (IFNγ) secretion in MS, and IFNγ administration induces exacerbations of disease. IFNγ expression is closely regulated by a number of cytokines produced by different cells of the immune system. Interleukin-12 (IL-12) is a major factor leading to Th1-type responses, including IFNγ secretion, and there is increased secretion of IL-12 in MS. IL-10 is a potent inhibitor of both IL-12 and IFNγ expression.Methods: The authors investigated cytokine production and proliferative responses of peripheral blood mononuclear cells stimulated with soluble anti-CD3 in healthy controls and patients with stable relapsing-remitting MS or progressive MS.Results: The authors found that T cell receptor–mediated IFNγ and IL-10 secretion were increased in progressive MS, whereas IL-4 and IL-2 secretion and lymphocyte proliferative responses were normal. Anti–IL-12 antibody suppressed raised IFNγ in progressive MS but did not affect raised IL-10. In addition, neutralization of endogenous IL-10 upregulated IFNγ in controls but not progressive MS. IL-10 was produced by CD4+ cells whereas IFNγ was produced by both CD4+ and CD8+ cells. There were no differences in IL-10 receptor expression in MS patients.Conclusions: These abnormalities in IL-10 regulation were not seen in the relapsing-remitting form of MS. Thus, the defect in regulation of both IL-12 and IFNγ production by endogenous IL-10 in progressive MS could be an important factor involved in the transition of MS from the relapsing to the progressive stage and has implications for treating MS patients with exogenous IL-10.