期刊
JOURNAL OF AUTOIMMUNITY
卷 24, 期 4, 页码 297-310出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2005.02.001
关键词
autoimmune; cytokine; prostaglandin; monocyte/macrophage; signal transduction
类别
资金
- NIAID NIH HHS [P01 AI42288, P01 AI042288] Funding Source: Medline
- NIDDK NIH HHS [R21 DK068082-01, K01 DK002947-05, KO1 DK02947, K01 DK002947-02, R21 DK068082, K01 DK002947-04, R21 DK068082-02, K01 DK002947-03, K01 DK002947-01A1, K01 DK002947] Funding Source: Medline
Autocrine granulocyte macrophage-colony stimulating factor (GM-CSF) sequentially activates intracellular components in monocyte/macrophage production of the pro-inflammatory and immunoregulatory prostanoid, prostaglandin E2 (PGE2). GMCSF first induces STAT5 signaling protein phosphorylation, then prostaglandin synthase 2 (COX2/PGS2) gene expression, and finally IL-10 production, to downregulate the cascade. Without activation, monocytes of at-risk, type I diabetic (TID), and autoimmune thyroid disease (AITD) humans, and macrophages of nonobese diabetic (NOD) mice have aberrantly high GM-CSF, PGS2, and PGE2 expression, but normal levels of IL-10. After GM-CSF stimulation, repressor STAT5A and B isoforms (8077 kDa) in autoimmune human and NOD monocytes and activator STAT5A (96-94 kDa) and B (94-92 kDa) isoforms in NOD macrophages stay persistently tyrosine phosphorylated. This STAT5 phosphorylation persisted despite treatment in vitro with IL-10, anti-GM-CSF antibody, or the JAK2/3 inhibitor, AG490. Phosphorylated STAT5 repressor isoforms in autoimmune monocytes had diminished DNA binding capacity on GAS sequences found in the PGS2 gene enhancer. In contrast, STAT5 activator isoforms in NOD macrophages retained their DNA binding capacity on these sites much longer than in healthy control strain macrophages. These findings suggest that STAT5 dysfunction may contribute to dysregulation of GM-CSF signaling and gene activation, including PGS2, in autoimmune monocytes and macrophages. (c) 2005 Elsevier Ltd. All rights reserved.
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