Interleukin-1 beta Induces MUC2 Gene Expression and Mucin Secretion via Activation of PKC-MEK/ERK,and PI3K in Human Airway Epithelial Cells

Abstract

Interleukin 1beta(IL-1beta), a proinflammatory cytokine, is related with inflammatory diseases and it up-regulates MUC2 gene expression and mucin secretion. This study was designed to investigate the signal transduction pathway of the IL-1beta-mediated MUC2 gene expression and mucin secretion in human airway epithelial cells. In cultured human airway NCI-H292 epithelial cells, the steady state of the mRNA level of MUC2 gene expression and mucin secretion induced by IL-1beta were determined by reverse transcriptase-polymerase chain reaction (RT-PCR), enzyme immunoassay, and immunoblot analysis. To observe the signal pathway of the IL-1beta-mediated MUC2 gene expression and mucin secretion, we used several specific inhibitors. PD98059 (MEK/ERK inhibitor) suppressed IL-1beta-mediated MUC2 gene expression and mucin secretion, while SB203580 (p38 inhibitor) did not. Ro31-8220 (PKC inhibitor) inhibited IL-1beta-mediated MUC2 gene expression and mucin secretion. It inhibited ERK phosphorylation, but did not inhibit p38 phosphorylation. LY294002 (PI3K inhibitor) also suppressed MUC2 expression, but did not inhibit any MAPKs phosphorylation. These results suggest that the IL-1beta-mediated MUC2 gene expression and mucin secretion in NCI-H292 cells are regulated through activation of the PKC-MEK/ERK pathway, and that PI3K is also involved in the IL-1beta-mediated MUC2 gene expression and mucin secretion.

Regulation of Airway Mucin Gene Expression

“…Another report revealed that IL-1β's stimulation of MUC2 occurs through the protein kinase C (PKC) and ERK pathways (49). In addition, this report also revealed that phosphoinositol 3-kinase (PI3K) inhibitors could partly block the induction of MUC2 without affecting ERK phosphorylation (49). This finding suggests that IL-1β's effect occurs through a parallel PI3K/AKT pathway (49).…”

“…In addition, this report also revealed that phosphoinositol 3-kinase (PI3K) inhibitors could partly block the induction of MUC2 without affecting ERK phosphorylation (49). This finding suggests that IL-1β's effect occurs through a parallel PI3K/AKT pathway (49). IL-4 can induce MUC2 expression in NCI-H292 cells as well as in colon cell lines (50,51).…”

“…In one report, a retinoic acid receptor (RAR)-α antagonist could inhibit the induction of MUC2 by IL-1β and TNF-α, suggesting that IL-1β and TNF-α act partly through RAR pathways (48). Another report revealed that IL-1β's stimulation of MUC2 occurs through the protein kinase C (PKC) and ERK pathways (49). In addition, this report also revealed that phosphoinositol 3-kinase (PI3K) inhibitors could partly block the induction of MUC2 without affecting ERK phosphorylation (49).…”

Differential expression of gastric MUC5AC in colonic epithelial cells: TFF3-wired IL1 β/Akt crosstalk-induced mucosal immune response againstShigella dysenteriaeinfection

“…IL-1b alone and in combination with LPS, can induce the overexpression of mucins in airway epithelial cells, goblet cells and murine biliary epithelial cells (Kim et al, 2002;Levine et al, 1995;Li et al, 1998;Dohrman et al, 1998;Zen et al, 2002;Perdomo et al, 1994;Zychlinsky et al, 1994;Raqib et al, 1995). S. dysenteriae infection causes a severe inflammation in the colon, which is triggered by extensive production of proinflammatory cytokines such as tumor necrosis factor alpha (TNFa) and IL-1b, which have been found in the stool and plasma of patients with acute shigellosis (Perdomo et al, 1994;Zychlinsky et al, 1994;Raqib et al, 1995;Kim et al, 2002).…”

“…Expression of the MUC2 gene in NCI-H292 human airway epithelial cells is mediated by interleukin-1b (IL-1b) through the activation of protein kinases PKC, MEK, ERK and PI3K (Kim et al, 2000;Kim et al, 2002;Perrais et al, 2002). IL-4 induces gene expression of MUC5AC and MUC4 in goblet cell metaplasia in vitro and in vivo (Temann et al, 1997;Dabbagh et al, 1999;Damera et al, 2006).…”