IL-17 Selectively Down-Regulates TNF-α-Induced RANTES Gene Expression in Human Colonic Subepithelial Myofibroblasts

Abstract

IL-17 enhances the TNF-α-induced IL-6 and IL-8 secretion in human colonic subepithelial myofibroblasts. In this study, we investigated how IL-17 modulates RANTES secretion in these cells. TNF-α potently induced RANTES secretion, but IL-17 dose-dependently inhibited the TNF-α-induced RANTES secretion. This was also observed at the mRNA level. Even after pretreatment with TNF-α for 12 h, the inhibitory effect of IL-17 was detectable. IL-17 did not affect the TNF-α-induced stability of the RANTES gene. IL-17 significantly decreased the TNF-α-induced increase in RANTES promoter activity, and IL-17 actually blocked the TNF-α-induced RANTES gene transcription. EMSAs demonstrated that IL-17 did not modulate the TNF-α-induced NF-κB DNA-binding activity, but markedly decreased TNF-α-induced IFN regulatory factor-1 (IRF-1) DNA-binding activity. Because cooperation between NF-κB and IRF-1 is important in the TNF-α-induced RANTES gene expression, the major mechanism mediating the inhibitory effect of IL-17 may be achieved by the inhibition of IRF-1 DNA-binding activity.

Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells

“…In addition, consistent with results reported previously with other cells (23,24), IL-17 also represses CCL5 expression by HT-29 cells. CXCR3 is expressed on Th1 but not Th2 or Th17 cells; thus the CXCR3 ligands CXCL10 and 11 are selectively chemotactic for Th1 cells (28).…”

“…In contrast, our results indicate that CXCL10 is encoded by a very stable mRNA, the decay of which is not affected by IL-17. Rather, the negative effect of IL-17 on CXCL10 gene expression occurs via transcriptional repression, in agreement with the previously reported repression by IL-17 of CCL5 gene transcription (23).…”

“…11). CCL5 gene transcription is also repressed by IL-17 (23), and the CCL5 promoter has an NF-B site with two ISREs located upstream of this site. (Fig.…”

“…Whereas TNF-␣ induces transcription of the genes for CXCL1 and CXCL8 by activating the NF-B signaling pathway, IL-17 appears to act mainly by stabilizing their mRNAs (19,20). Intriguingly, however, IL-17 negatively regulates TNF-␣-elicited production of other chemokines including CCL5 (RANTES) (23,24), CX3CL1 (fractalkine) (25), and CCL27 (cutaneous T cell-attracting chemokine or CTACK) (26). Moreover, in a mouse model of allergic asthma, IL-17 functions as a negative regulator by repressing expression of the eosinophil chemokine CCL11 (eotaxin) and Th2 chemokine CCL17 (thymus-and activation-regulated chemokine or TARC) (27).…”

IRF-1 reverts the transformed phenotype of oncogenically transformed cells in vitro and in vivo

“…IRF-1 exerts its effects by DNA binding and transactivation (Kirchhoff et al, 1993). However, activities like those induced by IL-17 or E6/E7 abolish or reduce its DNA binding and thus decrease the expression of IRF-1-induced genes (Park et al, 2000;Andoh et al, 2002). IRF-1 induces the transcription of a number of genes that exert growth inhibitory effects.…”