17β-estradiol inhibits the production of RANTES in human keratinocytes

Abstract

A chemokine, regulated upon activation, normal T cell expressed and secreted (RANTES) attracts T helper-1 cells and macrophages. The production of RANTES is enhanced in keratinocytes of psoriatic skin lesions, which may contribute to the inflammatory infiltrate. It is known that estrogen regulates the natural course of psoriasis. We examined the in vitro effects of 17β-estradiol on RANTES production by human keratinocytes. 17β-estradiol inhibited tumor necrosis factor-α or interleukin-1β-induced RANTES secretion, mRNA expression, and promoter activity in keratinocytes, and these effects of 17β-estradiol were counteracted by estrogen receptor antagonist ICI 182 780. Two nuclear factor κB elements on RANTES promoter were required for tumor necrosis factor-α or interleukin-1β-induced transcription and involved in the inhibition by 17β-estradiol. 17β-estradiol inhibited nuclear factor KB transcriptional activity, whereas it did not inhibit DNA binding of nuclear factor KB or phosphorylation or degradation of the inhibitor of nuclear factor κB α in tumor necrosis factor-α or interleukin-1β-stimulated keratinocytes. 17β-estradiol-induce inhibition of nuclear factor κB transcriptional activity and RANTES promoter activity was rescued by overexpression of a coactivator cyclic AMP response element-binding protein (CREB) or nuclear factor κB p65 but not by steroid receptor coactivator-1 or nuclear factor κB p50. The overexpression of CREB-binding protein rescued 17β-estradiol-induced inhibition of transcription mediated by a chimeric protein, GAL4-p65286-551, which contained GAL4 DNA binding domain fused to C-terminal transactivating domain of p65 (amino acids 286-551). The transfection of estrogen receptor α or estrogen receptor 1β into estrogen receptor-negative SKBR3 cells resulted in 17β-estradiol-mediated inhibition of transcription via GAL4-p65286-551. These results suggest that 17β-estradiol-bound estrogen receptor may inhibit nuclear factor κB-dependent transcription of RANTES gene by competing with p65 for limiting amounts of CREB-binding protein.