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R. Mahdi, S.H. Jackson, C. Yu, C.E. Egwuagu; Dendritic Cell Maturation is Accompanied by a Change from STAT6 to STAT1 Utilization and by Differential Expression of Suppressor of Cytokine Signaling (SOCS) . Invest. Ophthalmol. Vis. Sci. 2003;44(13):743.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Dendritic cell (DC) maturation is triggered by endocytosis of microbial products and differentiation from the immature DC (iDC) into mature DC (mDC) phenotype is accompanied by significant alterations in the pattern of gene transcription, cell morphology and function. Signals that regulate the maturation process derive from pro-inflammatory cytokines such as IL-4 and GM-CSF. In this study, we have tested the hypothesis that selective repression of iDC-specific pathways in mDC is mediated by suppressor of cytokine signaling (SOCS) proteins. Methods:Bone-marrow derived mouse DC precursors (pDC) were differentiated into immature DC (iDC) by stimulation with IL-4 and GM-CSF for 3 days. mDC were generated by LPS stimulation of iDC. Cytokine-activated pathways were characterized by by Western blotting and EMSA. Analysis and quantitation of SOCS gene expression was by Northern blotting and real-time PCR. Results:Neither STAT1 nor STAT6 is activated in pDC. Stimulation of pDC by IL-4 induces constitutive activation of STAT6 but not STAT1: GM-CSF had no effects on STAT activation. Low constitutive SOCS expression is detected in pDC and differentiation into iDC results in upregulated expression of SOCS2 (>10 folds) and to a lesser extent SOCS1 and SOCS3. In contrast, maturation into mDC is accompanied by: 1) inhibition of STAT6 phosphorylation; 2) GM-CSF-mediated dramatic increase in STAT1 activation; 3). Induction of a 17 fold increase in SOCS1 expression by IL-4. Conclusions:Mutually exclusive utilization of STAT6 and STAT1 signaling pathways by iDC and mDC respectively, suggest that activation of STAT6 by IL-4 may be important for iDC function and that down-regulation of this pathway may be essential to permit manifestation of mDC function. Conversely, activation of STAT1 pathways by GM-CSF appears to be essential for mDC but not iDC functions. Thus, constitutive and inducible SOCS expression by pDC, iDC and mDC, suggest that differential repression of STAT1 or STAT6 signaling in iDC and mDC, respectively may be mediated in part by SOCS proteins.
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