IL-10 receptor dysfunction in macrophages during chronic inflammation

The immunosuppressive activity of interleukin-10 (IL-10) makes this cytokin e a potentially important clinical tool to reduce inflammatory responses in various diseases. Its efficacy as a therapeutic modality is dependent on t he responsiveness of immune cells. We report that macrophages from mice chr onically infected with the LP-BM5 retrovirus had a reduced capacity to resp ond to IL-10 in vitro. The ability of IL-10 to inhibit lipopolysaccharide-i nduced production of tumor necrosis factor (TNF) alpha and IL-6 was signifi cantly reduced in both alveolar and peritoneal macrophages from infected ve rsus uninfected mice. IL-10 hyporesponsiveness was not related to direct in fection by the retrovirus, because bone marrow-derived macrophages infected in vitro with LP-BM5 were as responsive to IL-10 as were uninfected bone m arrow-derived macrophages. TNF-alpha appeared to contribute to development of IL-10 hyporesponsiveness, because exposure of normal macrophages to TNF- alpha but not interferon-gamma reduced macrophage responsiveness to IL-10. Reverse transcriptase-PCR and flow cytometry demonstrated normal expression of the alpha and beta chains of the IL-10 receptor in macrophages from inf ected mice, suggesting that IL-10 hyporesponsiveness is not related to a ch ange in receptor expression. The potential role of reduced IL-10 responsive ness in the chronicity of inflammation in this and other diseases is discus sed.