Endotoxin tolerance (ET) is a complex protective mechanism against endotoxin shock. The looped CLP-19 peptide derived from Limulus anti-LPS peptide induced the ET phenomenon but the molecular mechanism has yet to be fully elucidated. Here, we confirmed that CLP-19 attenuated upon LPS stimulated pro inflammatory factor secretion of TNF-alpha and IL-6 but increased anti-inflammatory factor production of IL-10 in dose-and time-dependent manners. CLP-19 also inhibited subsequent LPS stimulated expression of TLR4 on the cell membrane. Moreover, the CLP-19 inhibited degradation of the inhibitor of NF-kappa B (lam and 1013) and reduced LPS induced NF-kappa B activity, but not of effects on expression of MyD88 and TRAF-6. Finally CLP-19 significantly increased survival of lethal LPS shock mouse models with significantly less pathological injury to lung. These findings collectively suggest that CLP-19 induces ET phenomenon involved inhibition of NF-kappa B activation. In conclusion, this study has revealed a novel function of CLP-19 that appears to represent a potential therapeutic agent for clinical treatment of septic shock. (C) 2016 Elsevier Inc. All rights reserved.