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Inhibition of lipopolysaccharide-induced macrophage IL-12 production by Leishmania mexicana amastigotes: the role of cysteine peptidases and the NF-kappaB signaling pathway

Cameron, P. and McGachy, H.A. and Anderson, M. and Paul, A. and Coombs, G.H. and Mottram, J.C. and Alexander, J. and Plevin, R.J. (2004) Inhibition of lipopolysaccharide-induced macrophage IL-12 production by Leishmania mexicana amastigotes: the role of cysteine peptidases and the NF-kappaB signaling pathway. Journal of Immunology, 173 (5). pp. 3297-3304. ISSN 0022-1767

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Abstract

Infection with lesion-derived Leishmania mexicana amastigotes inhibited LPS-induced IL-12 production by mouse bone marrow-derived macrophages. This effect was associated with expression of cysteine peptidase B (CPB) because amastigotes of CPB deletion mutants had limited ability to inhibit IL-12 production, whereas preincubation of cells with a CPB inhibitor, cathepsin inhibitor IV, was able to suppress the effect of wild-type amastigotes. Infection with wild-type amastigotes resulted in a time-dependent proteolytic degradation of IB and IB and the related protein NF-B. This effect did not occur with amastigotes of CPB deletion mutants or wild-type promastigotes, which do not express detectable CPB. NF-B DNA binding was also inhibited by amastigote infection, although nuclear translocation of cleaved fragments of p65 NF-B was still observed. Cysteine peptidase inhibitors prevented IB, IB, and NF-B degradation induced by amastigotes, and recombinant CPB2.8, an amastigote-specific isoenzyme of CPB, was shown to degrade GST-IB in vitro. LPS-mediated IB and IB degradation was not affected by these inhibitors, confirming that the site of degradation of IB, IB, and NF-B by the amastigotes was not receptor-driven, proteosomal-mediated cleavage. Infection of bone marrow macrophages with amastigotes resulted in cleavage of JNK and ERK, but not p38 MAPK, whereas preincubation with a cysteine peptidase inhibitor prevented degradation of these proteins, but did not result in enhanced protein kinase activation. Collectively, our results suggest that the amastigote-specific cysteine peptidases of L. mexicana are central to the ability of the parasite to modulate signaling via NF-B and consequently inhibit IL-12 production.