Synergistic induction of arginase I transcription in macrophage cells

Induction of arginase I (ARGI) plays a role in many inflammatory diseases. Thus, elucidation of the mechanisms involved in ARGI induction may identify targets for therapeutic intervention. Inducers of ARGI include interleukin‐4 (IL‐4) and agents that elevate cAMP. IL‐4 and cAMP each induce ARGI in macrophages, but together they synergize to dramatically induce ARGI. The objective of this study was to determine the basis for the synergism. Immunohistochemistry showed that the degree of ARGI induction reflected differences in numbers of ARGI‐expressing cells rather than in the degree of ARGI expression per cell. Previous work showed that IL‐4 induction required binding of the transcription factors STAT6 and C/EBPβ to the IL‐4 response element of the ARGI gene. We used chromatin immunoprecipitation (ChIP) to test the hypothesis that synergistic induction involves coordinate binding of both transcription factors to the IL‐4 response element. ChIP analysis showed increased binding of both STAT6 and C/EBPβ in response to IL‐4 alone, increased binding only of C/EBPβ in response to cAMP alone, but greatly increased binding of both factors in response to IL‐4 + cAMP. These results indicate that synergistic induction of ARGI transcription is a stochastic process that involves a major increase in coordinate binding of both transcription factors to the IL‐4 response element of the ARGI gene. (Supported by grants from NIH).