Journal
JOURNAL OF PHARMACY AND PHARMACOLOGY
Volume 57, Issue 2, Pages 213-218Publisher
WILEY
DOI: 10.1211/0022357055443
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The metalloantibiotic bacitracin is a known inhibitor of protein disulfide isomerase (PDI). The disulfide-linked interleukin-12 (IL-12) alphabeta-heterodimer and beta(2)-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 beta(2)-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 alpha- and beta-chain. Similar to bacitracin, N-acetylcysteine blocked alphabeta- and beta(2)-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.
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