Macrophage production of inflammatory mediators is potently inhibited by a butyric acid derivative demonstrated to inactivate antigen-stimulated T cells.
The butyric acid derivative, 2-(4-morpholynl) ethyl butyrate hydrochloride (MEB), has been reported to induce antigen-specific T cell unresponsiveness and to block T cell-mediated graft-versus-host disease. As a potential therapeutic agent, it was important to determine the effects of MEB on other cells that contribute to immunopathology. Accordingly, we tested the effects of MEB on macrophage functions. MEB did not affect macrophage viability, phagocytic activity, or the activation-induced up-regulation of molecules associated with antigen presentation: MHC-II, CD86, CD40, or ICAM-1. However, MEB potently inhibited activation-induced production of inflammatory mediators, including tumor necrosis factor-alpha (TNF-alpha), IL-6, chemokine CCL2 and nitric oxide (NO). MEB inhibited the induction of NO synthase (NOS2), which is necessary for inducible NO, and inhibited nuclear translocation of NFkappaB, suggesting that MEB interferes with the signaling pathway involved in NOS2 induction. Thus, while inducing specific T cell unresponsiveness, MEB also exerts anti-inflammatory activity by acting on macrophages to suppress production of cytokines and NO.
Soderberg
Lee S F
LS
Department of Microbiology and Immunology, College of Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham Steet, Little Rock, AR 72205, USA. soderbergless@uams.edu
Boger
Susan
S
Fifer
E Kim
EK
Gilbert
Kathleen M
KM
D000818:Animals; D000941:Antigens / Q000276:immunology*; D015703:Antigens, CD / Q000096:biosynthesis; D051940:B7-2 Antigen; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology*; D019013:CD40 Antigens / Q000096:biosynthesis; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D005802:Genes, MHC Class II / Q000187:drug effects; D006633:Histamine Antagonists / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology*; D016328:NF-kappa B / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects*
C412896:2-(4-morpholinyl)ethyl butyrate; D000941:Antigens; D015703:Antigens, CD; D051940:B7-2 Antigen; D002087:Butyrates; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D006633:Histamine Antagonists; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D009025:Morpholines; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide