The metallopeptide antibiotic bacitracin inhibits interleukin-12 alphabeta and beta2 secretion.
The metalloantibiotic bacitracin is a known inhibitor of protein disulfide isomerase (PDI). The disulfide-linked interleukin-12 (IL-12) alphabeta-heterodimer and beta2-homodimer forms are crucial mediators of cell-mediated immune responses and inflammatory reactions. Bacitracin was found to potently block secretion of both the alphabeta- and beta2-dimer forms of IL-12, while it did not affect secretion of the beta-monomer. This inhibition coincided with a reduction in the intracellular amount of PDI found in complex with the beta-chain during intracellular transit. Bacitracin did not affect mRNA levels of the alphabeta- and beta-chain. Similar to bacitracin, N-acetylcysteine blocked alphabeta- and beta2-secretion as well as PDI-beta-chain complex formation. Thus, blocking PDI or shifting the endoplasmic reticulum towards a more reduced status disrupts the oxidative folding pathway or assembly of IL-12 dimer forms. The assembly stage of cytokines in the endoplasmic reticulum may represent a novel target for pharmacological intervention.
Alloza
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Applied Genomics Research Group, School of Pharmacy, Queen's University of Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
Vandenbroeck
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D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001414:Bacitracin / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D008667:Metalloproteins / Q000737:chemistry / Q000494:pharmacology; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors / Q000502:physiology; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008667:Metalloproteins; D012333:RNA, Messenger; D001414:Bacitracin; D018664:Interleukin-12; D019704:Protein Disulfide-Isomerases; D000111:Acetylcysteine