Role of IRAK1 on TNF-induced Proliferation and NF-κB Activation in Human Bone Marrow Mesenchymal Stem Cells

In this study, we determined the effect of TNF-alpha on hBMSCs proliferation as well as the role of IL-1 receptor-associated kinase 1 (IRAK1) on TNF-alpha signaling. Western blot analysis revealed that TNF-alpha treatment increased the phosphorylation of IRAK1 in hBMSCs. The downregulation of IRAK1 inhibited TNF-alpha-induced NF-kappa B activation and COX-2 expression. TNF-alpha treatment increased hBMSCs proliferation in a dose-dependent manner and increased ERK, JNK, and NF-kappa B activity. U0126, an ERK inhibitor, decreased hBMSCs proliferation and significantly blocked TNF-alpha -induced hBMSCs proliferation. In cells with IRAK1 or TRADD downregulation, the U0126 treatment inhibited hBMSCs proliferation and significantly suppressed TNF-alpha-induced hBMSCs proliferation. The downregulation of IRAK1 or TRADD inhibited TNF-alpha-induced ERK and JNK activation, and hBMSCs proliferation. Inhibition of NF-kappa B by decoy oligonucleotides reduced the TNF-alpha-induced hBMSCs proliferation. Immunoprecipitation analysis showed that IRAK1 does not physically interact with TNF receptor 1 (INFR1) even in the presence of TNF-alpha. Suppression of IRAK1 binding protein (IRAK1BP1) inhibited TNF-alpha-induced increase of the proliferation and ERK1 phosphorylation of hBMSCs in the presence of TNF-alpha. Our data indicate that TNF-alpha modulates hBMSCs proliferation through ERK signaling pathways, and that IRAK1 plays an important role in TNF-alpha-induced NF-kappa B activation in hBMSCs. Copyright (c) 2012 S. Karger AG, Basel