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R. Mahdi, C.–R. Yu, X. Liu, A. Amadi–Obi, I. Gery, C. Egwuagu; STAT1 Is a Master Regulator of Th1, Th2, Th3 Cytokine Gene Expression in Differentiating T–Helper Cells . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4541.
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© ARVO (1962-2015); The Authors (2016-present)
Initiation of adaptive immune response and T–helper cell (Th) lineage commitment is regulated by IFNγ and IL–4 through activation of STAT1 or STAT6 pathways and subsequent imprinting of Th1/Th2 cytokine secretion pattern. Although positive and negative regulatory effects of IFNγ on Th1 and Th2 cytokine expression, respectively, requires STAT1, little is known of the role played by STAT signals. Here we have investigated STAT1 effects on proinflammatory cytokines expression in STAT1–deficient or normal mice and during experimental autoimmune uveitis (EAU).
EAU was induced in STAT1+/+ or STAT1–/– C57BL/6 mice by immunization with IRBP in CFA. Naive lymph node and splenic Th (>95% CD4+, CD62hi, CD25low) from normal or STAT1–/– mice were stimulated with anti–CD3/CD28 abs and subjected to 2 cycles of Th1/Th2 polarization. Cytokine expression/secretion was analyzed by ELISA, intracellular staining or real–time RT–PCR. Cellular proliferation was assessed by 3H–thymidine incorporation and EAU was confirmed by fundoscopy and histology.
Naïve STAT1–/– Th exhibit an activated phenotype with elevated levels of Th1 (IFNγ, TNFα), Th2 (IL–4, IL–5, IL–13) and Th3 (IL–10) cytokines. However, this cytokine expression pattern is observed mainly in first cycle of polarization. Although expression of Th2/Th3 cytokines remain elevated in STAT1–/– Th2 cells, IFNγ and TNFα is significantly decreased in Th1–polarized STAT1–/– cells. In addition, twice as much IFNγ is secreted during EAU by STAT1–/–Th compared to their WT counterpart, further underscoring inhibitory effect of STAT1 on Th1 cytokine expression. Interestingly, STAT1–/–Th are characterized by global inhibition of all members of the suppressor of cytokine signaling (SOCS) family of proteins analyzed.
Our results suggest that maintenance of naive Th cells in a quiescent or inactive state requires STAT1 signals and that this transcription factor is a master regulator of inflammatory cytokine expression in differentiating Th cells. Our data further suggests that the activated phenotype and elevation of Th1, Th2 and Th3 cytokines in STAT1–/–Th cells results from drastic inhibition of SOCS genes.
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