Interferon-γ differentially regulates TGF-β1 and TGF-β2 expression in human retinal pigment epithelial cells through JAK-STAT pathway

✍ Scribed by Chandrasekharam N. Nagineni; Karthik S. Cherukuri; Veena Kutty; Barbara Detrick; John J. Hooks

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 365 KB
• Volume: 210
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.20839

✦ Synopsis

Abstract

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.