A20 is critical for the induction of Pam3CSK4-tolerance in monocytic THP-1 cells.
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.
Medical Research Center, Changsha Central Hospital, Changsha, Hunan, China.
Jinyue
J
Hu
Cancer Center, Changsha Central Hospital, Changsha, Hunan, China.
Guihua
G
Wang
Medical Research Center, Changsha Central Hospital, Changsha, Hunan, China.
Xueting
X
Liu
Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
Lina
L
Zhou
Medical Research Center, Changsha Central Hospital, Changsha, Hunan, China.
Manli
M
Jiang
Tuberculosis Research Center, Changsha Central Hospital, Changsha, Hunan, China.
Li
L
Yang
D002460:Cell Line; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D007108:Immune Tolerance; D053583:Interleukin-1beta / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D055666:Lipopeptides / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D009687:Nuclear Proteins / Q000502:physiology*; D051192:Receptors, Pattern Recognition / Q000276:immunology; D015398:Signal Transduction; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004268:DNA-Binding Proteins; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D055666:Lipopeptides; D009687:Nuclear Proteins; C508075:Pam(3)CSK(4) peptide; D051192:Receptors, Pattern Recognition; D014409:Tumor Necrosis Factor-alpha; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3