Leishmania mexicana promastigotes inhibit macrophage IL-12 production via TLR-4 dependent COX-2, iNOS and arginase-1 expression

Shweash, M., Adrienne McGachy, H., Schroeder, J., Neamatallah, T., Bryant, C.E., Millington, O., Mottram, J.C. , Alexander, J. and Plevin, R. (2011) Leishmania mexicana promastigotes inhibit macrophage IL-12 production via TLR-4 dependent COX-2, iNOS and arginase-1 expression. Molecular Immunology, 48(15-16), pp. 1800-1808. (doi: 10.1016/j.molimm.2011.05.013)

Abstract

The effects of Leishmania mexicana metacyclic promastigotes upon MAP kinase signalling in mouse bone marrow macrophages and subsequent expression of the disease regulatory proteins iNOS and COX-2 were studied. At a ratio of 5:1, promastigotes caused a marked increase in phosphorylation of the three major MAP kinases, ERK, p38 and JNK. MAP kinase signalling was substantially reduced in TLR-4^−/− but not TLR-2^−/− deficient macrophages and completely abolished in double TLR-2/4^−/− macrophages. A similar outcome was observed using cysteine peptidase B deficient amastigotes. Furthermore, whilst promastigotes had no independent effect on iNOS or COX-2 expression, they prolonged the induction of these proteins stimulated by LPS and enhanced PGE₂ and NO production. Induction of COX-2 and iNOS was also TLR-4 dependent. Blockade of either PGE₂ or NO production with indomethacin or l-NAME reversed promastigote inhibition of LPS induced IL-12 production. Promastigotes also increased macrophage arginase-1 expression and enhanced arginase activity, both of which were substantially reduced in TLR-4 but not TLR-2 deficient macrophages. Surprisingly, arginase inhibition by Nor-NOHA also caused a reversal of promastigote mediated inhibition of macrophage IL-12 production. These data demonstrate for the first time the role of TLR-4 in mediating the effects of L. mexicana promastigotes on MAP kinase activation, up-regulation of COX-2, iNOS as well as arginase-1 expression in macrophages and further shows that PGE₂, NO and arginase activity all contribute substantially to the inhibition of host cell IL-12 production.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Mottram, Professor Jeremy
• Authors: Shweash, M., Adrienne McGachy, H., Schroeder, J., Neamatallah, T., Bryant, C.E., Millington, O., Mottram, J.C., Alexander, J., and Plevin, R.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Molecular Immunology
• Journal Abbr.: Mol. Immunol.
• ISSN: 0161-5890
• Published Online: 12 June 2011