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Interferon‐γ differentially regulates TGF‐β1 and TGF‐β2 expression in human retinal pigment epithelial cells through JAK‐STAT pathway
Author(s) -
Nagineni Chandrasekharam N.,
Cherukuri Karthik S.,
Kutty Veena,
Detrick Barbara,
Hooks John J.
Publication year - 2007
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.20839
Subject(s) - secretion , transforming growth factor , biology , cytokine , messenger rna , retinal , transforming growth factor beta , microbiology and biotechnology , retinal pigment epithelium , medicine , endocrinology , chemistry , immunology , gene , biochemistry
Retinal pigment epithelium (RPE) and transforming growth factor‐β (TGF‐β) have been shown to be involved in various retinal diseases. We have studied the role of inflammatory cytokines on the expression and secretion of TGF‐β in human RPE cells (HRPE). Confluent cultures of HRPE derived from donor eyes were used. RT‐PCR analyses showed that TNF‐α and IL‐1β increased the mRNA levels of both TGF‐β1 and TGF‐β2. IFN‐γ enhanced constitutively expressed, as well as, TNF‐α‐and IL‐1β‐induced TGF‐β1 mRNA levels but decreased TGF‐β2 mRNA. The effects of these cytokines on TGF‐β1 and TGF‐β2 secretion correlated with the mRNA levels. TGF‐β1 was always produced as the latent form while 21–31% of TGF‐β2 was in the active form. IFN‐γ reduced the production of active form of TGF‐β2 to 4–9%. TGF‐β3 secretion was not detectable under any of the conditions. The Real‐Time PCR analysis of TGF‐β mRNAs confirmed the observed results. The TGF‐β1 and TGF‐β2 secretion was induced by TGF‐β2 and TGF‐β1, respectively. Under these conditions, the contrasting effects of IFN‐γ on TGF‐β1 and TGF‐β2 secretion were also observed. JAK inhibitor selectively inhibited IFN‐γ induced TGF‐β1 secretion and mRNA levels while reversing the inhibitory effects of IFN‐γ on TGF‐β2. Analyses of transcription factor activity strongly indicated the role of STAT‐1 but not NFκB, C‐Myc, C‐Jun, SP‐1, MEF‐2. Our data demonstrate that IFN‐γ differentially regulates constitutively expressed, as well as, cytokine‐induced TGF‐β1 and TGF‐β2 mRNA levels and secretion of TGF‐βs by HRPE. J. Cell. Physiol. 210: 192–200, 2007. © 2006 Wiley‐Liss, Inc.