SUPPRESSORS OF CYTOKINE SIGNALING AND IL-10 INHIBITORY EFFECT IN LYME DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lyme disease, caused by the spirochete Borrelia burgdorferi, is an inflammatory disease. Inflammation, as induced by the spirochete, plays a major role in disease pathogenesis. The anti-inflammatory cytokine IL-10 has been shown to be a key regulator of inflammatory responses in Lyme disease, by controlling the production and function of various pro-inflammatory cytokines. Recently we observed that B. burgdorferi together with IL-10 additively induced the expression of the suppressor of cytokine signaling (SOCS)1 and 3 in macrophages. SOCS1/SOCS3 expression correlated with the IL-10-mediated inhibition of several pro-inflammatory cytokines. We hypothesized that the expression of SOCS induced by B. burgdorferi and IL-10 in macrophages is functionally important in the IL-10-mediated control of inflammation in macrophages. We used RNAi to silence the SOCS3 gene in mouse J774 macrophages stimulated with either live B. burgdorferi (Bb) or lipidated outer surface protein A (L-OspA) alone, or each stimulant together with IL-10. Using a SOCS3 specific pool of 4 siRNA molecules we achieved up to 79% knockdown of SOCS3 gene expression in cells transfected with the SOCS3 siRNA as compared to cells transfected with a nontargeting control siRNA, as assessed by real-time RT-PCR. IL-6 production was increased in culture supernatants with stimulants combined with IL-10 and SOCS3 siRNA as compared to those containing control siRNA. Taken together, these data suggest that SOCS3 may be involved in the IL-10 control of inflammation in macrophages.