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. We have shown that interleukin-10 (IL-10) inhibits inflammatory cytokines produced by macrophages in response to Borrelia burgdorferi or its lipoproteins. The mechanism by which IL-10 exerts this anti-inflammatory effect is still unknown. Recent findings indicate that suppressors of cytokine signaling (SOCS) proteins are induced by cytokines and Toll-like receptor (TLR)-mediated stimuli, and in turn can down-regulate cytokine and TLR signaling in macrophages. Because it is known that SOCS are induced by IL-10, and B. burgdorferi/lipoproteins most likely interact via TLR2 or the heterodimers TLR2/1 and/or TLR2/6, we hypothesize that SOCS are induced by IL-10 and B. burgdorferi/lipoproteins in macrophages, and may mediate the inhibition by IL-10 of concomitantly elicited cytokines. We report here that mouse J774 macrophages incubated with IL-10 and added B. burgdorferi spirochetes (freeze-thawed, live or sonicated), lipidated outer surface protein A (L-OspA) but not unlipidated OspA augmented their SOCS1/SOCS3 mRNA expression, with SOCS3 being the more abundant. Pam3Cys, a synthetic lipopeptide, also induced SOCS1/SOCS3 under these conditions. Neither endogenous IL-10 nor the translation inhibitor cycloheximide blocked SOCS1/SOCS3 induction by B. burgdorferi/lipoproteins, indicating the expression of other genes is not required. Co-stimulation of macrophages with IL-10 and B. burgdorferi/lipoproteins also augmented the expression of SOCS1/SOCS3 proteins. This correlated with the IL-10-mediated inhibition of the inflammatory cytokines IL-1?, IL-6, IL-12p40, IL-18 and TNF-?. Our data are evidence to suggest that the capacity of IL-10 to inhibit inflammatory cytokines elicited by B. burgdorferi/lipoproteins in macrophages depends on SOCS, and may provide a possible mechanism for the anti-inflammatory effects of IL-10 in this cont