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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058047-03
Application #
6984102
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Rathbun, Gary
Project Start
2003-12-15
Project End
2008-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
3
Fiscal Year
2006
Total Cost
$413,213
Indirect Cost
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Weaver, Brian K; Bohn, Erwin; Judd, Barbi A et al. (2007) ABIN-3: a molecular basis for species divergence in interleukin-10-induced anti-inflammatory actions. Mol Cell Biol 27:4603-16
Pan, Qilin; Kravchenko, Vladimir; Katz, Alex et al. (2006) NF-kappa B-inducing kinase regulates selected gene expression in the Nod2 signaling pathway. Infect Immun 74:2121-7