Signal transduction activator of transcription 5 (STAT5) dysfunction in autoimmune monocytes and macrophages

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). GM-CSF first induces STAT5 signaling protein phosphorylation, then p...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of autoimmunity Vol. 24; no. 4; pp. 297 - 310
Main Authors:	Litherland, S.A., Xie, T.X., Grebe, K.M., Davoodi-Semiromi, A., Elf, J., Belkin, N.S., Moldawer, L.L., Clare-Salzler, M.J.
Format:	Journal Article
Language:	English
Published:	London Elsevier Ltd 01-06-2005 Elsevier
Subjects:	Adolescent Adult Animals Autoimmune Autoimmune Diseases - immunology Autoimmune Diseases - pathology Biological and medical sciences Cells, Cultured Child Cytokine DNA-Binding Proteins - immunology Female Fundamental and applied biological sciences. Psychology Fundamental immunology Gene Expression Regulation - immunology General aspects Humans Immunopathology Macrophages - immunology Macrophages - pathology Male Medical sciences Mice Mice, Inbred NOD Middle Aged Milk Proteins - immunology Monocyte/macrophage Monocytes - immunology Monocytes - pathology Prostaglandin Signal transduction Signal Transduction - immunology STAT5 Transcription Factor Trans-Activators - immunology Transcriptional Activation Tumor Suppressor Proteins Monocyte/macrophage Signal transduction Autoimmune Prostaglandin Cytokine Autoimmunity Immunopathology Monocyte Transcription Arachidonic acid derivatives Cytokine: Prostaglandin Immunology Activator Transcription factor STAT5 Dysfunction Eicosanoid Macrophage
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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). GM-CSF 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 1 diabetic (T1D), 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 (80–77 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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Current address: NIH-NIAID, Bldg 4, Rm 209, 4 Center Dr., Bethesda, MD 20892-0440. Current address: 1505 Liatris Lane, Raleigh, NC 27613, USA.
ISSN:	0896-8411 1095-9157
DOI:	10.1016/j.jaut.2005.02.001