IL-10 Receptor Signaling That Regulates Innate Immunity

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): IL-10 is a cytokine that has contrasting effects on immune system function. It promotes humoral immunity by enhancing proliferation, survival, and differentiation of B cells, but inhibits innate immunity by ablating production of pro-inflammatory cytokines from myeloid cells and from lymphocytes. IL-10manifests its effects by binding to a specific receptor expressed on many different immune cells. Our previous work helped define the IL-10 receptor and demonstrated that the JAK-STAT signaling path way is required for all IL-10 receptor stimulated functions. A structure-function analysis on the intracellular domain (ICD) of the IL-10 receptor ligand binding chain (IL10R1) revealed that, whereas all IL-10's actions required the presence of an ICD region containing the receptor docking site for the transcription factor Stat3, IL-10's anti-inflammatory effects selectively required the additional presence of the IL-10R1carboxyl terminus. Based on this observation we asked whether we could identify IL-10 induced genes whose regulation required both functionally important regions of the IL-10R1 ICD. Using representation difference analysis, we identified and cloned a novel IL-10-induced gene (denoted TIGER) whose induction fulfills these criteria and have generated a mouse that lacks the TIGER gene locus. In Specific Aim 1, we propose to study the TIGER-/- mouse to assess the physiologic function of this gene. IL-10 dependent induction of TIGER requires new protein synthesis and we currently do not know whether TIGER expression is required for IL-10's anti-inflammatory effects. Thus in Specific Aim 2 we will conduct microchip-based gene profiling experiments to identify a panel of IL-10-regulated genes whose induction is both independent of protein synthesis (i.e. are immediate-early genes) and requires both functionally important regions of the IL-10R1 ICD. These genes will then be used in Specific Aim 3 to define the signal transduction pathway that the IL-10 receptor uses to selectively inhibit inflammatory and/or innate immune responses. This work should identify the molecular basis for IL-10's anti-inflammatory effects and should thus provide us with novel strategies to nonspecifically enhance resistance to infectious agents by interfering with this signaling pathway.