IL-4 and IL-13 play important roles in immune-mediated inflammation through effects on a variety of cell populations. These actions depend in part on modulation of chemokine gene expression and include induction of new genes as well as inhibition of responses to IFNy. Changes in chemokine expression are now recognized to significantly impact the host-tumor relationship by controlling both tumor and lukocyte trafficking. The signaling and transcription factor STAT6 plays a requisite role in much (though not all) IL- 4/IL-13-stimulated change in gene expression. Mechanisms involved hi suppression of gene expression, particularly, remain poorly understood.
In Specific Aim 1 we will examine IL-4/IL-13-mediated STAT6- dependent inhibitory action and will test the hypothesis that suppression depends upon specific protein- protein interactions mediated through the STAT6 TAD. We have recently observed that IFNy-induced expression of a subset of chemokine genes is markedly enhanced STAT6 deficient cells.
In Specific Aim 2 we will explore the mechanistic basis for this apparently ligand-independent inhibitory activity of STAT6 by evaluating the structural features of STAT6, the signaling pathways, and gene promoter sequences that are required. IFNy and IL-4are capable of regulating gene expression (both positive and negative) through pathways that operate independently of and/or in addition to STAT1 or STAT6, respectively. Using Affymetrix oligonucleotide microarray analyses we have identified a small subset of chemokine genes whose expression can be induced comparably by IL-4 in macrophages obtained from both STAT6+/+ and STAT6-/- mice.
In Specific Aim 3 we will examine the mechanisms for IL-4/IL-13-mediated, STAT6-independent induction of MCP-2 and MCP-5 by analysis of IL-4Ra receptor structure, signaling events, and promoter sequences responsible for specific gene behavior. In concert, the results of the proposed studies will lead to mechanistic understanding of the means through which distinct cell types develop highly diverse responses to these important immunoregulatory cytokines.
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