Celastrol modulates inflammation through inhibition of the catalytic activity of mediators of arachidonic acid pathway: Secretory phospholipase A2group IIA, 5-lipoxygenase and cyclooxygenase-2.
Elevated production of arachidonic acid (AA)-derived pro-inflammatory eicosanoids due to the concerted action of secretory phospholipase A2group IIA (sPLA2IIA), 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) is a common feature of many inflammatory disorders. Hence, modulation of the bioactivity of these 3 enzymes is an important strategy to control inflammation. However, the failure of drugs specific for an individual enzyme (sPLA2IIA-, 5-LOX- or COX-2) and the success of 5-LOX/COX-2 dual inhibitors in effectively controlling inflammation in clinical trials prompted us to evaluate a common inhibitor for sPLA2IIA, 5-LOX and COX-2 enzymes. Celastrol, a quinone methide triterpene, was selected in this regard through molecular docking studies. We provide the first evidence for celastrol's ability to inhibit the catalytic activity of sPLA2IIA, 5-LOX and COX-2 enzymes. Celastrol significantly inhibited the catalytic activity of sPLA2IIA (IC50=6μM) in vitro, which is independent of substrate and calcium concentration. In addition, celastrol inhibited the catalytic activities of 5-LOX (IC50=5μM) and COX-2 (IC50=20μM) in vitro; sPLA2IIA-induced edema and carrageenan-induced edema in mice; and lipopolysaccharide-stimulated production of PGE2in human neutrophils. Thus, celastrol modulates inflammatory responses by targeting multiple enzymes of AA pathway.
Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, India.
Vikram
V
Joshi
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Shivaprasad H
SH
Venkatesha
Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India.
Chandrasekaran
C
Ramakrishnan
Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, India.
Ankanahalli N
AN
Nanjaraj Urs
Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, India.
Vilas
V
Hiremath
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA; Division of Rheumatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Kamal D
KD
Moudgil
Centre of Advanced Study in Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai, Tamil Nadu, India.
Devadasan
D
Velmurugan
Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysuru, Karnataka, India. Electronic address: vishmy@yahoo.co.uk.
Bannikuppe Sannanaik
BS
Vishwanath
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002384:Catalysis / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004487:Edema / Q000378:metabolism; D054501:Group II Phospholipases A2 / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000494:pharmacology*
D052246:Cyclooxygenase 2 Inhibitors; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; D054501:Group II Phospholipases A2; D015232:Dinoprostone; C050414:celastrol; D002118:Calcium
Arachidonic acid; Celastrol; Cyclooxygenase; Inflammation; Lipoxygenase; Phospholipase A(2)