TL1A induces the expression of TGF-β-inducible gene h3 (βig-h3) through PKC, PI3K, and ERK in THP-1 cells

beta ig-h3, an extracellular matrix protein involved in various biological processes including cellular growth, differentiation, adhesion, migration, and angiogenesis, has been shown to be elevated in various inflammatory processes. Death receptor 3 (DR3), a member of the TNF-receptor superfamily that is expressed on T cells and macrophages, is involved in the regulation of inflammatory processes through interaction with its cognate ligand, TNF-like ligand IA (TL1A). In order to find out whether the TL1A-induced inflammatory activation of macrophages is associated with the up-regulation of beta ig-h3 expression, the human acute monocytic leukemia cell line (THP-1) was stimulated with either recombinant human TL1A- or DR3-specific monoclonal antibodies. Stimulation of DR3 up-regulated the intracellular levels as well as the secretion of beta ig-h3. Utilization of various inhibitors and Western blot analysis revealed that activation of protein kinase C (PKC), extracellular signal-regulated kinase (ERK), phosphoinositide kinase-3 (PI3K), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) is required for TL1A-induced beta ig-h3 expression. PKC appears to be the upstream regulator of PI3K since the presence of PKC inhibitor blocked the phosphorylation of AKT without affecting ERK phosphorylation. On the other hand, suppression of either PI3K or ERK activity resulted in the suppression of I kappa B phosphorylation. These findings indicate that TL1A can regulate the inflammatory processes through modulation of the beta ig-h3 expression through two separate pathways, one through PKC and PI3K and the other through ERK, which culminates at NF-kappa B activation. (C) 2010 Elsevier Inc. All rights reserved.