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A more recent version of this article appeared on September 1, 2004

Published online before print June 24, 2004
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1003526

Received for publication October 30, 2003.
Revised May 7, 2004.
Accepted for publication May 26, 2004.

Article

Role of endogenous IL-10 in LPS-induced STAT3 activation and IL-1 receptor antagonist gene expression

Virginia S. Carl , Jitendra K. Gautam , Laurey D. Comeau , and Michael F. Smith Jr.@

University of Virginia Health System, Departments of Medicine, Digestive Health Center of Excellence and Microbiology, Charlottesville

@ To whom correspondence should be addressed. E-mail: mfs3k{at}virginia.edu.


  Abstract

The regulation of secretory interleukin (IL)-1 receptor antagonist (sIL-1Ra) in response to IL-10 is unique. In contrast to most cytokines, the lipopolysaccharide (LPS)-induced expression of the sIL-1Ra gene is enhanced by concomitant treatment with IL-10. Cotreatment of RAW 264.7 cells with IL-10 + LPS resulted in at least a twofold increase in sIL-1Ra promoter activity and mRNA expression compared with LPS alone; IL-10 alone had no effect on promoter activity or mRNA expression. Examination of sIL-1Ra mRNA expression in bone marrow-derived macrophages (BMDM) resulted in identical results. Transfection of RAW 264.7 cells with the sIL-1Ra/luc reporter and a dominant-negative signal transducer and activator of transcription (STAT)3 (Y705A) expression plasmid inhibited the enhanced response induced by exogenous IL-10 in the presence of LPS. The presence of a functional STAT3-bininding site within the proximal sIL-1Ra promoter was demonstrated. As IL-10 is produced by LPS-stimulated macrophages, a role for endogenously produced IL-10 in the response of the sIL-1Ra gene to LPS was suggested. This was confirmed in IL-10-deficient BMDM, which when compared with normal BMDM, had significantly decreased LPS-induced sIL-1Ra mRNA levels that could be restored by exogenously provided IL-10, which induced a fivefold increase of LPS-induced IL-1Ra mRNA in cells from IL-10-/- BMDM. Western blot analysis of phosphorylated STAT3 from wild-type and IL-10-/- BMDM and IL-10 neutralization experiments demonstrated a role for endogenously produced IL-10 in the LPS-induced STAT3 activity. Together, these results demonstrate that endogenously produced IL-10 plays a significant role in LPS-induced sIL-1Ra gene expression via the activation of STAT3.

Key Words: lipopolysacharide • cytokine • macrophage






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