Fasciola hepatica fatty acid binding protein inhibits TLR4 activation and suppresses the inflammatory cytokines induced by lipopolysaccharide in vitro and in vivo.

ABSTRACT: TLR4, the innate immunity receptor for bacterial endotoxins, plays a pivotal role in the induction of inflammatory responses. There is a need to develop molecules that block either activation through TLR4 or the downstream signaling pathways to inhibit the storm of inflammation typically elicited by bacterial LPS, which is a major cause of the high mortality associated with bacterial sepsis. We report in this article that a single i.p. injection of 15 ?g fatty acid binding protein from Fasciola hepatica (Fh12) 1 h before exposure to LPS suppressed significantly the expression of serum inflammatory cytokines in a model of septic shock using C57BL/6 mice. Because macrophages are a good source of IL-12p70 and TNF-?, and are critical in driving adaptive immunity, we investigated the effect of Fh12 on the function of mouse bone marrow-derived macrophages (bmM?s). Although Fh12 alone did not induce cytokine expression, it significantly suppressed the expression of IL-12, TNF-?, IL-6, and IL-1? cytokines, as well as inducible NO synthase-2 in bmM?s, and also impaired the phagocytic capacity of bmM?s. Fh12 had a limited effect on the expression of inflammatory cytokines induced in response to other TLR ligands. One mechanism used by Fh12 to exert its anti-inflammatory effect is binding to the CD14 coreceptor. Moreover, it suppresses phosphorylation of ERK, p38, and JNK. The potent anti-inflammatory properties of Fh12 demonstrated in this study open doors to further studies directed at exploring the potential of this molecule as a new class of drug against septic shock or other inflammatory diseases.

SUBMITTER: Martin I 

PROVIDER: S-EPMC4390499 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature