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

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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 recently demonstrated that stimulation of mouse J774 macrophages with either live Borrelia burgdorferi spirochetes (Bb) or Bb purified outer surface lipoprotein (L-OspA) alone or combined with IL-10 augmented the expression of the suppressor of cytokine signaling (SOCS)1 and SOCS3 in these cells. We hypothesized that the expression of SOCS1/SOCS3 induced by B. burgdorferi alone or together with IL-10 in macrophages is functionally important in the control of inflammation during the course of Lyme disease; SOCS1/SOCS3 would act as direct modulators of inflammatory cytokine signaling in macrophages. To test this hypothesis, we examined the ability of SOCS to inhibit the activation and DNA binding activities of phosphorylated STAT (signal transducer and activator of transcription) 1 protein in response to IFN-gamma. We focused on IFN-gamma signaling because this cytokine plays a pivotal role in the activation of macrophages during the initial phase of the immune response. Live Bb and L-OspA alone or combined with IL-10 did not activate the phosphorylation of STAT1 in macrophages at all time points examined (0-60 mins). However, these stimulants inhibited pSTAT1 activation by 2- to 5-fold in response to IFN-g. This correlated with the enhanced expression of SOCS1/SOCS3 induced in these cells by live Bb and L-OspA. Live Bb combined with IL-10, L-OspA alone or combined with IL-10 significantly (P 0.002 to 0004) inhibited the nuclear translocation of pSTAT1 in macrophages in response to IFN-gamma. SOCS overexpression in macrophages had no effect on nitric oxide (NO) production by IFN-gamma, suggesting that SOCS is not a mediator of NO production by IFN-gamma in macrophages. This study demonstrates that SOCS1/SOCS3 induced by B. burgdorferi may functionally suppress macrophage activation and interfere with the host immune response during the early phase of disease.