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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

Inhibition of Lipopolysaccharide-Induced Macrophage IL-12 Production by Leishmania Mexicana Amastigotes: The Role of Cysteine Peptidases and the NF-kappaB Signaling Pathway

Pamela Cameron, Adrienne McGachy, Mary Anderson, Andrew Paul, Graham H Coombs, Jeremy C Mottram, James Alexander, Robin Plevin

J Immunol. 2004 Sep 1;173(5):3297-304.

PMID: 15322192

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 IkappaBalpha and IkappaBbeta and the related protein NF-kappaB. This effect did not occur with amastigotes of CPB deletion mutants or wild-type promastigotes, which do not express detectable CPB. NF-kappaB DNA binding was also inhibited by amastigote infection, although nuclear translocation of cleaved fragments of p65 NF-kappaB was still observed. Cysteine peptidase inhibitors prevented IkappaBalpha, IkappaBbeta, and NF-kappaB degradation induced by amastigotes, and recombinant CPB2.8, an amastigote-specific isoenzyme of CPB, was shown to degrade GST-IkappaBalpha in vitro. LPS-mediated IkappaBalpha and IkappaBbeta degradation was not affected by these inhibitors, confirming that the site of degradation of IkappaBalpha, IkappaBbeta, and NF-kappaB 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-kappaB and consequently inhibit IL-12 production.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1638411-A	p38 MAP Kinase Inhibitor IV		1638-41-1	Price

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