Abstract
The epithelium‐specific ETS (ESE)‐1 transcription factor is induced in chondrocytes by interleukin‐1β (IL‐1β). We reported previously that early activation of EGR‐1 by IL‐1β results in suppression of the proximal COL2A1 promoter activity by displacement of Sp1 from GC boxes. Here we report that ESE‐1 is a potent transcriptional suppressor of COL2A1 promoter activity in chondrocytes and accounts for the sustained, NF‐κB‐dependent inhibition by IL‐1β. Of the ETS factors tested, this response was specific to ESE‐1, since ESE‐3, which was also induced by IL‐1β, suppressed COL2A1 promoter activity only weakly. In contrast, overexpression of ETS‐1 increased COL2A1 promoter activity and blocked the inhibition by IL‐1β. These responses to ESE‐1 and ETS‐1 were confirmed using siRNA‐ESE1 and siRNA‐ETS1. In transient cotransfections, the inhibitory responses to ESE‐1 and IL‐1β colocalized in the −577/−132 bp promoter region, ESE‐1 bound specifically to tandem ETS sites at −403/−381 bp, and IL‐1‐induced binding of ESE‐1 to the COL2A1 promoter was confirmed in vivo by ChIP. Our results indicate that ESE‐1 serves a potent repressor function by interacting with at least two sites in the COL2A1 promoter. However, the endogenous response may depend upon the balance of other ETS factors such as ETS‐1, and other IL‐1‐induced factors, including EGR‐1 at any given time. Intracellular ESE‐1 staining in chondrocytes in cartilage from patients with osteoarthritis (OA), but not in normal cartilage, further suggests a fundamental role for ESE‐1 in cartilage degeneration and suppression of repair. J. Cell. Physiol. 215: 562–573, 2008. © 2007 Wiley‐Liss, Inc.