REGULATION OF SOCS EXPRESSION IN MACROPHAGES IN RESPONSE TO BORRELIA AND IL-10

点击翻译按钮获取中文摘要

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. Inflammation, as induced by the spirochete Borrelia burgdorferi in multiple organs, plays a major role in disease pathogenesis, but its regulation is not understood We recently showed that mouse J774 macrophages incubated with IL-10 and added B. burgdorferi spirochetes (freeze-thawed, live or sonicated) or lipidated outer surface protein A (L-OspA) augmented their suppressor of cytokine signaling (SOCS)1 and SOCS3 expression, with SOCS3 being the more abundant. This temporally correlated with the IL-10-mediated inhibition of expression of several pro-inflammatory cytokines. We hypothesized that augmentation of SOCS expression by co-stimulation compared to stimulation with individual stimulants led either to reinforcement of a common signaling pathway or convergence of different signaling pathways for optimal SOCS expression. To begin to address this hypothesis, we used murine cDNA microarray to investigate mediators of SOCS induction in macrophages. J774 macrophages were co-stimulated with IL-10 and sonicated B. burgdorferi spirochetes and RNA samples were collected at 2, 4 and 24 hr post-stimulation for microarray analyses. Based on a fold-change cut-off criterion of 3, we observed over 500 up-regulated genes in macrophages, chief amongst which was the SOCS3 gene (log2 fold change of 5-6). The gene expression data revealed both unique and overlapping sets of genes at all time points. Further Gene Ontology analysis revealed amongst genes with altered microarray profiles, the over-representation of genes encoding mediators from TLR, JAK/STAT and p38 MAPK signaling pathways. These pathways are known to be involved in the induction of SOCS, thus suggesting that more than one pathway maybe involved in SOCS induction in macrophages co-stimulated with IL-10 and sonicated spirochetes.