STAT3 PARTICIPATES IN TRANSCRIPTIONAL ACTIVATION OF THE C-REACTIVE PROTEIN GENE BY INTERLEUKIN-6

Interlenkin-6 (IL-6) is the major cytokine inducing transcription of h uman C-reactive protein (CRP) during the acute phase response. STAT (s ignal transducers and activators of transcription) family members, rec ently shown to be important mediators of the effects of many cytokines including IL-6, generally induce their effects by binding to palindro mic sequences with TT(N)(5)AA motifs. We report an IL-6 responsive ele ment in the proximal region of the human CRP 5'-flanking region that b ears a TT(N)(4)AA motif, which we have termed CRP acute phase response element (CRP-APRE). In Hep3B cells, IL-6 but not interferon-gamma was capable of activating CAT constructs driven by the CRP promoter conta ining CRP-APRE. Overexpressed STAT3 was able to transactivate CRP-chlo ramphenicol acetyltransferase constructs through the CRP-APRE and was able to enhance endogenous CRP mRNA accumulation in response to IL-6. STAT3 (or an antigenically related molecule) bound to the CRP-APRE in response to IL-6. Overexpression of STAT3 in the presence of IL-6 was capable of inducing expression of a construct consisting of the CRP-AP RE and a minimal thymidine kinase promoter lacking a C/EBP site. Taken together, these findings indicate that STAT3 participates in the tran scriptional activation of CRP in response to IL-6.