IL-22 Enhances TNF-α- and IL-1-Induced CXCL8 Responses by Intestinal Epithelial Cell Lines

IL-22 is known to induce intestinal epithelial cells (IECs) to produce the chemokine CXCL8. However, IECs exist in a cytokine network during mucosal inflammation, such that IL-22 must act in concert with potent pro-inflammatory cytokines like TNF-α and IL-1. Our studies show that IL-22 alone increased CXCL8 secretion from HT-29 cells, but the levels were minimal compared to that of the cells treated with TNF-α or IL-1 only. More significantly, co-stimulation with IL-22 and TNF-α enhanced both CXCL8 secretion and mRNA levels well over that of TNF-α stimulation alone. A similar enhancing effect was seen with IL-22- and IL-1-stimulated CXCL8 secretion. The enhancing effect of IL-22 on TNF-α-induced CXCL8 secretion was then determined to require the p38 MAPK, but not STAT1/3, PI3K, Akt, c-Jun N-terminal kinase, ERK, or IκBα. These experiments indicate that more significant effect of IL-22 on IECs responses may not be in inducing CXCL8 by itself, but in enhancing TNF-α- and IL-1-induced CXCL8 secretion to augment the contribution of IECs to local inflammatory responses.