The metallopeptide antibiotic bacitracin inhibits interleukin-12 αβ and β2 secretion
- 1 February 2005
- journal article
- Published by Oxford University Press (OUP) in Journal of Pharmacy and Pharmacology
- Vol. 57 (2) , 213-218
- https://doi.org/10.1211/0022357055443
Abstract
The metalloantibiotic bacitracin is a known inhibitor of protein disulfide isomerase (PDI). The disulfide-linked interleukin-12 (IL-12) αβ-heterodimer and β2-homodimer forms are crucial mediators of cell-mediated immune responses and inflammatory reactions. Bacitracin was found to potently block secretion of both the αβ- and β2-dimer forms of IL-12, while it did not affect secretion of the β-monomer. This inhibition coincided with a reduction in the intracellular amount of PDI found in complex with the β-chain during intracellular transit. Bacitracin did not affect mRNA levels of the α- and β-chain. Similar to bacitracin, N-acetylcysteine blocked αβ- and β2-secretion as well as PDI-β-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.Keywords
This publication has 20 references indexed in Scilit:
- Protein disulfide isomerase suppresses the transcriptional activity of NF-κBBiochemical and Biophysical Research Communications, 2004
- Inhibiting cytokines of the interleukin-12 family: recent advances and novel challengesJournal of Pharmacy and Pharmacology, 2004
- Protein Disulfide Isomerase, a Component of the Estrogen Receptor Complex, Is Associated withChlamydia trachomatisSerovar E Attached to Human Endometrial Epithelial CellsInfection and Immunity, 2002
- The Conserved Helix C Region in the Superfamily of Interferon-γ/Interleukin-10-related Cytokines Corresponds to a High-affinity Binding Site for the HSP70 Chaperone DnaKPublished by Elsevier ,2002
- THIOL ANTIOXIDANTS INHIBIT THE FORMATION OF THE INTERLEUKIN-12 HETERODIMER: A NOVEL MECHANISM FOR THE INHIBITION OF IL-12 PRODUCTIONCytokine, 2002
- Hormone Binding by Protein Disulfide Isomerase, a High Capacity Hormone Reservoir of the Endoplasmic ReticulumJournal of Biological Chemistry, 2001
- Interleukin‐12 Antagonist Activity of Mouse Interleukin‐12 p40 Homodimer in Vitro and in VivoAnnals of the New York Academy of Sciences, 1996
- Mouse interleukin‐12 (IL‐12) p40 homodimer: a potent IL‐12 antagonistEuropean Journal of Immunology, 1995
- Protein disulphide isomerase: building bridges in protein foldingTrends in Biochemical Sciences, 1994
- Inhibition of a reductive function of the plasma membrane by bacitracin and antibodies against protein disulfide-isomerase.Proceedings of the National Academy of Sciences, 1993