Journal
JOURNAL OF IMMUNOLOGY
Volume 194, Issue 8, Pages 3924-3936Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1401182
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Funding
- National Institutes of Health [1SC1AI096108-01A2]
- Minority Biomedical Research Support-Research Initiative for Scientific Enhancement of the University of Puerto Rico [R25GM061838]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [SC1AI096108] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R25GM061838, P20GM103642] Funding Source: NIH RePORTER
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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 mu 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-alpha, and are critical in driving adaptive immunity, we investigated the effect of Fh12 on the function of mouse bone marrow-derived macrophages (bmM Phi s). Although Fh12 alone did not induce cytokine expression, it significantly suppressed the expression of IL-12, TNF-alpha, IL-6, and IL-1 beta cytokines, as well as inducible NO synthase-2 in bmM Phi s, and also impaired the phagocytic capacity of bmMFs. 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.
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