title: 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 μg 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-α, and are critical in driving adaptive immunity, we investigated the effect of Fh12 on the function of mouse bone marrow-derived macrophages (bmMΦs). Although Fh12 alone did not induce cytokine expression, it significantly suppressed the expression of IL-12, TNF-α, IL-6, and IL-1β cytokines, as well as inducible NO synthase-2 in bmMΦs, and also impaired the phagocytic capacity of bmMΦs. 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.
authors.affiliation: Laboratory of Immunology and Molecular Parasitology, Department of Microbiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico 00936-5067.
authors.forename: Ivelisse
authors.initials: I
authors.lastname: Martin
authors.affiliation: Laboratory of Immunology and Molecular Parasitology, Department of Microbiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico 00936-5067.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Cabán-Hernández
authors.affiliation: Laboratory of Immunology and Molecular Parasitology, Department of Microbiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico 00936-5067.
authors.forename: Olgary
authors.initials: O
authors.lastname: Figueroa-Santiago
authors.affiliation: Laboratory of Immunology and Molecular Parasitology, Department of Microbiology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico 00936-5067 ana.espino1@upr.edu.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Espino
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology; D005210:Fasciola hepatica / Q000276:immunology*; D050556:Fatty Acid-Binding Proteins / Q000276:immunology / Q000494:pharmacology*; D005260:Female; D015801:Helminth Proteins / Q000276:immunology / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; D050556:Fatty Acid-Binding Proteins; D015801:Helminth Proteins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases