Heterotrimeric G Protein Gα₁₃-Induced Induction of Cytokine mRNAs Through Two Distinct Pathways in Cardiac Fibroblasts

Abstract

Overexpression of constitutively active (CA)-Gα₁₃ significantly increased the expression of interleukin (IL)-1β and IL-6 mRNAs and proteins in rat cardiac fibroblasts. IL-1β mRNA induction by CA-Gα₁₃ was suppressed by diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, but not by BAPTA-AM, an intracellular Ca²⁺ chelator. In contrast, IL-6 mRNA induction by CA-Gα₁₃ was suppressed by BAPTA-AM but not by DPI. However, both IL-1β and IL-6 mRNA induction was suppressed by nuclear factor κB (NF-κB) inhibitors. The CA-Gα₁₃-induced NF-κB activation was suppressed by DPI and BAPTA-AM, but not C3 toxin and the Rho-kinase inhibitor Y27632. IL-6 mRNA induction by CA-Gα₁₃ was suppressed by SK&F96365 (1-[β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole hydrochloride), an inhibitor of receptor-activated nonselective cation channels, and the expression of CA-Gα₁₃ increased basal Ca²⁺ influx. These results suggest that Gα₁₃ regulates IL-1β mRNA induction through the reactive oxygen species-NF-κB pathway, while it regulates IL-6 mRNA induction through the Ca²⁺-NF-κB pathway.