Penicillin conjugates to interferon-gamma and reduces its activity: a novel drug-cytokine interaction.
Beta-lactam antibiotics are the class of drug most frequently associated with IgE-mediated allergy but the mechanisms underlying this response are poorly understood. IFN-gamma is a key cytokine in immunity with regulatory actions on monocytes, NK cells, epithelial cells, and T and B lymphocytes. IFN-gamma promotes Th1 responses and inhibits Th2- and IgE-mediated responses. In this study we show, by Western blotting, that the prototype beta-lactam benzylpenicillin (BP) conjugates to human IFN-gamma but not to IL-4. The interaction of BP with IFN-gamma inhibited the cytokine's detection by immunoassay and impaired its activity, as assessed in three different assays: upregulation of MHC molecules on monocytes plus induction of nitric oxide synthesis and expression of monocyte chemoattractant protein-1 mRNA by epithelial cells. This is the first reported example of a direct drug-cytokine interaction and suggests a mechanism by which penicillin may disrupt IFN-gamma-dependent immune responses and promote allergy.
Brooks
B M
BM
Department of Pharmacology and Therapeutics, University of Liverpool, Ashton Street, Liverpool L69 3GE, United Kingdom. ptbmb@liv.ac.uk
Flanagan
B F
BF
Thomas
A L
AL
Coleman
J W
JW
D002460:Cell Line; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D004336:Drug Antagonism; D004342:Drug Hypersensitivity / Q000209:etiology; D004797:Enzyme-Linked Immunosorbent Assay; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology*; D015847:Interleukin-4 / Q000378:metabolism; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000276:immunology; D009569:Nitric Oxide / Q000096:biosynthesis; D010400:Penicillin G / Q000378:metabolism* / Q000494:pharmacology*; D010406:Penicillins / Q000378:metabolism* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D015854:Up-Regulation
D018932:Chemokine CCL2; D006684:HLA-DR Antigens; D010406:Penicillins; D012333:RNA, Messenger; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma; D010400:Penicillin G