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 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 (80-77kDa) in autoimmune human and NOD monocytes and activator STAT5A (96-94kDa) and B (94-92kDa) 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.
Litherland
S A
SA
Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, 100275 JHMHC, 1600 SW Archer Road, Gainesville, FL 32610, USA. litherla@pathology.ufl.edu
Xie
T X
TX
Grebe
K M
KM
Davoodi-Semiromi
A
A
Elf
J
J
Belkin
N S
NS
Moldawer
L L
LL
Clare-Salzler
M J
MJ
D000293:Adolescent; D000328:Adult; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D004268:DNA-Binding Proteins / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D008894:Milk Proteins / Q000276:immunology*; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000276:immunology*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins