Interleukin-10 inhibits expression of both interferon alpha- and interferon gamma-induced genes by suppressing tyrosine phosphorylation of STAT1

Interleukin-10 (IL-10) helps maintain polarized T-helper cells in a T-helpe r lymphocyte 2 (Th2) phenotype. Part of this process involves the preventio n of the development of Th1 cells, which are a primary source of interferon gamma (IFN gamma), a potent activator of monocytes and an inhibitor of Th2 proliferation. Because monocytes and macrophages are important mediators o f Th1-type responses, such as delayed-type hypersensitivity. we sought to d etermine if IL-10 could directly mediate inhibition of IFN gamma- and IFN a lpha-induced gene expression in these cells. Highly purified monocytes were incubated with IL-10 for 60 to 90 minutes before the addition of IFN gamma or IFN alpha. IL-10 preincubation resulted in the inhibition of gene expre ssion for several IFN-induced genes, such as IP-10, ISG54, and intercellula r adhesion molecule-1. The reduction in gene expression resulted from the a bility of IL-10 to suppress IFN-induced assembly of signal transducer and a ctivator of transcription (STAT) factors to specific promoter motifs on IFN alpha- and IFN gamma-inducible genes. This was accomplished by preventing the IFN-induced tyrosine phosphorylation of STAT1, a component of both IFN alpha- and IFN gamma-induced DNA binding complexes. Therefore, IL-10 can di rectly inhibit STAT-dependent early response gene expression induced by bot h IFN alpha and IFN gamma in monocytes by suppressing the tyrosine phosphor ylation of STAT1. This may occur through the ability of IL-10 to induce exp ression of the gene, suppressor of cytokine signaling 3 (SOCS3). This is a US government work. There are no restrictions on its use.