ABSTRACT
5(S),6(R)-7-trihydroxymethyl heptanoate (BML-111) is an lipoxin A4 receptor agonist, which modulates the immune response and attenuates hemorrhagic shock-induced acute lung injury. However, the role of BML-111 in sepsis and in the intestinal mucosal barrier are not well understood. Therefore, the present study was designed to investigate the effect of BML-111 on the intestinal mucosal barrier in a rat model of sepsis. Furthermore, the molecular mechanism of action of BML-111 was evaluated. The cecal ligation and puncture-induced rat model of sepsis was constructed, and BML-111 was administered at three different doses. The results revealed that BML-111 suppressed the elevation of the pro-inflammatory cytokines tumor necrosis factor-α and interleukin-6, while enhancing the elevation of the anti-inflammatory cytokine transforming growth factor-ß in the intestine. In addition, BML-111 significantly upregulated rat defensin-5 mRNA expression levels and downregulated the induction of cell apoptosis as well as caspase-3 activity in the intestine. All these results demonstrated that BML-111 exerted protective effects on the intestinal mucosal barrier in sepsis. Further, it was indicated that alterations in the expression of toll-like receptor (TLR)2 and TLR4 may be one of the molecular mechanisms underlying the protective effect of BML-111. The present study therefore suggested that BML-111 may be a novel therapeutic agent for sepsis.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Defensins/agonists , Heptanoic Acids/pharmacology , Intestinal Mucosa/drug effects , Sepsis/drug therapy , Animals , Apoptosis , Caspase 3/genetics , Caspase 3/immunology , Defensins/genetics , Defensins/immunology , Disease Models, Animal , Gene Expression Regulation , Humans , Immunity, Mucosal/drug effects , Injections, Intraperitoneal , Interleukin-6/genetics , Interleukin-6/immunology , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Male , Rats , Rats, Sprague-Dawley , Sepsis/genetics , Sepsis/immunology , Sepsis/pathology , Signal Transduction , Toll-Like Receptor 2/genetics , Toll-Like Receptor 2/immunology , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/immunology , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/immunology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
Retrocyclin-1 (RC-100) is a cyclic octadecapeptide whose primary structure is based on the sequence of an expressed human theta-defensin pseudogene. RC-111 has the same amino acid sequence as RC-100 and is also cyclic, but its residues are placed in reverse order along the peptide's backbone. We quantified the effects of RC-100 and RC-111 on HIV-1 infection using HIV clones that expressed green fluorescent protein. Whereas 0.2 microg/ml of RC-100 inhibited infection of CD4-positive cells by approximately 80%, its retro-analogue significantly enhanced infection of the cells. RC-100 and RC-111 also demonstrate their effects in HIV infection of CD4-negative cells. Whereas 40 ng/ml of RC-111 significantly enhanced infection of CD4-negative cells by HIV-1, RC-100 demonstrated significant inhibition of HIV infection with a concentration of approximately 10 microg/ml. RC-111ox, an acyclic variant of RC-111 with a beta-hairpin structure, also enhanced HIV-1 infection, but did so less effectively than cyclic RC-111. The divergent actions of RC-100 and RC-111 show that topology and polarity of theta-defensin peptides can determine their effect on HIV infection. The ability of RC-111 to enhance HIV-1 infection might prove useful in developing peptides that can enhance gene delivery by HIV-based lentiviral vectors.
