Migration inhibitory factor induces killing of Leishmania major by macrophages: dependence on reactive nitrogen intermediates and endogenous TNF-alpha.
Macrophage migration inhibitory factor (MIF) is a product of activated T cells, anterior pituitary cells, and macrophages. MIF plays an important role in LPS-induced shock and delayed-type hypersensitivity. Furthermore, MIF exhibits a proinflammatory spectrum of action, promoting TNF-alpha production by macrophages, and counter-regulates glucocorticoid suppression of cytokine production. Here, we report that purified recombinant MIF activates murine macrophages to kill Leishmania major, with maximal effects at concentrations above 1 microg/ml. This MIF-mediated activation is specific, since it can be blocked completely by anti-MIF mAb. The MIF-mediated activation is dependent on TNF-alpha produced endogenously by macrophages, because the administration of anti-TNF-alpha antiserum markedly reduced the MIF effect. No MIF-mediated activation was observed in macrophages derived from TNF receptor p55 knockout mice, thus demonstrating the requirement of the smaller TNF receptor molecule for autocrine TNF-alpha signaling. A highly specific inhibitor of the inducible nitric oxide synthase (iNOS), L-N6-(1-iminoethyl)lysine, dihydrochloride, also inhibited the action of MIF, suggesting an important role for iNOS in the antiparasitic properties of MIF. In line with this, no MIF-mediated activation was detected analyzing macrophages derived from iNOS-deficient mice. The effect of MIF was blocked completely by the macrophage-deactivating cytokines IL-10, IL-13, and TGF-beta. Finally, the expression of MIF mRNA and protein was up-regulated in lymph nodes of mice during the first week after infection with L. major. MIF therefore represents a cytokine involved not only in the recruitment of proinflammatory cells during infection but also in the complex regulation of the antimicrobial activity of these cells.
Jüttner
S
S
Institute of Clinical Microbiology and Immunology, University of Erlangen-Nürnberg, Germany.
Bernhagen
J
J
Metz
C N
CN
Röllinghoff
M
M
Bucala
R
R
Gessner
A
A
D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology; D018793:Interleukin-13 / Q000494:pharmacology; D018320:Leishmania major / Q000187:drug effects / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D018793:Interleukin-13; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse