A20 is critical for the induction of Pam3CSK4-tolerance in monocytic THP-1 cells

• Published in: PloS one Vol. 9; no. 1; p. e87528
• Main Authors: Hu, Jinyue, Wang, Guihua, Liu, Xueting, Zhou, Lina, Jiang, Manli, Yang, Li
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28.01.2014; Public Library of Science (PLoS)
• Subjects: A20 protein; Activation; Biology; Cell Line; Cellular signal transduction; Cross-tolerance; Cytokines; DNA-Binding Proteins - physiology; Down-Regulation; Enzymes; Gene expression; Gene transfer; Genes; Homeostasis; IL-1β; Immune response; Immune system; Immune Tolerance; Immunological tolerance; Inflammation; Inflammatory bowel disease; Interleukin-1beta - pharmacology; Intracellular Signaling Peptides and Proteins - physiology; JNK protein; Kinases; Ligands; Lipopeptides - immunology; Lipopolysaccharides; Medical research; Monocytes; Monocytes - immunology; NF-κB protein; Nuclear Proteins - physiology; Overexpression; Pharmacology; Proteins; Receptors, Pattern Recognition - immunology; Ribonucleic acid; RNA; RNA-mediated interference; Signal Transduction; Signaling; Stimulation; TLR1 protein; Toll-like receptors; Tumor Necrosis Factor alpha-Induced Protein 3; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; Tumor necrosis factor-α; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0087528

A20 functions to terminate Toll-like receptor (TLR)-induced immune response, and play important roles in the induction of lipopolysacchride (LPS)-tolerance. However, the molecular mechanism for Pam3CSK4-tolerance is uncertain. Here we report that TLR1/2 ligand Pam3CSK4 induced tolerance in monocytic THP-1 cells. The pre-treatment of THP-1 cells with Pam3CSK4 down-regulated the induction of pro-inflammatory cytokines induced by Pam3CSK4 re-stimulation. Pam3CSK4 pre-treatment also down-regulated the signaling transduction of JNK, p38 and NF-κB induced by Pam3CSK4 re-stimulation. The activation of TLR1/2 induced a rapid and robust up-regulation of A20, suggesting that A20 may contribute to the induction of Pam3CSK4-tolerance. This hypothesis was proved by the observation that the over-expression of A20 by gene transfer down-regulated Pam3CSK4-induced inflammatory responses, and the down-regulation of A20 by RNA interference inhibited the induction of tolerance. Moreover, LPS induced a significant up-regulation of A20, which contributed to the induction of cross-tolerance between LPS and Pam3CSK4. A20 was also induced by the treatment of THP-1 cells with TNF-α and IL-1β. The pre-treatment with TNF-α and IL-1β partly down-regulated Pam3CSK4-induced activation of MAPKs. Furthermore, pharmacologic inhibition of GSK3 signaling down-regulated Pam3CSK4-induced A20 expression, up-regulated Pam3CSK4-induced inflammatory responses, and partly reversed Pam3CSK4 pre-treatment-induced tolerance, suggesting that GSK3 is involved in TLR1/2-induced tolerance by up-regulation of A20 expression. Taken together, these results indicated that A20 is a critical regulator for TLR1/2-induced pro-inflammatory responses.