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

Background: MS is a chronic inflammatory disease of the CNS postulated to be a Th1 type cell-mediated autoimmune disease. There is increased interferon-gamma (IFN gamma) secretion in MS, and IFN gamma administration induces exacerbations of disease. IFN gamma 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 IFN gamma secretion, and there is increased secretion of IL-12 in MS. IL-10 is a potent inhibitor of both IL-12 and IFN gamma expression. Methods: The authors investigated cytokine production and proliferative responses of peripheral blood mononuclear cells stimulated with soluble anti-CDS in healthy controls and patients with stable relapsing-remitting MS or progressive MS. Results: The authors found that T cell receptor-mediated IFN gamma and IL-10 secretion were increased in progressive MS, whereas IL-4 and IL-2 secretion and lymphocyte proliferative responses were normal. Anti-IL-la antibody suppressed raised IFN gamma in progressive MS but did not affect raised IL-10. In addition, neutralization of endogenous IL-10 upregulated IFN gamma in controls but not progressive MS. IL-10 was produced by CD4+ cells whereas IFN gamma 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 IFN gamma 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.