title: Involvement of TACE in colon inflammation: a novel mechanism of regulation via SIRT-1 activation.
abstract: TNF-α converting enzyme (TACE) processes the membrane TNF-α to release the bioactive soluble TNF-α. Several evidences suggest the involvement of TNF-α and TACE in inflammatory bowel disease (IBD). Tissue inhibitor of metalloproteinase (TIMP)-3, an endogenous inhibitor of TACE, is positively associated with silent information regulator (SIRT)-1. We aimed to study the expression of TACE, TIMP-3 and SIRT-1 at different stages of colitis and how TACE is regulated in response to SIRT-1 activation. Acute colitis was induced by 3.5% dextran sulfate sodium (DSS) in drinking water for 5days and levels of cytokines and mRNA expression of TACE, TIMP-3 and SIRT-1 were measured in colon at different time intervals. Next, the effect of SIRT-1 activator (resveratrol) or a selective TACE inhibitor (compound 11p) treatment was evaluated. Elevated levels of TNF-α, interleukin (IL)-6, IL-1β, interferon (IFN)-γ and IL-17 were observed during DSS exposure phase which restored to the normal level after DSS removal. A significant increase in TACE and suppression in TIMP-3 and SIRT-1 mRNA level was observed during DSS exposure phase which reverts back to normal towards the remission phase. Treatment with resveratrol significantly elevated SIRT-1 and TIMP-3 and suppressed TACE mRNA expression and was associated with amelioration of disease. Furthermore, treatment with selective TACE inhibitor significantly suppressed body weight loss, disease activity index, colonic myeloperoxidase activity and the elevated levels of cytokines after DSS challenge. These results strongly emphasize the involvement of TACE in colon inflammation and inhibition of TACE directly or indirectly via SIRT-1 activation ameliorates colitis.
authors.affiliation: Dept. of Pharmacology, Zydus Research Centre, Moraiya, Ahmedabad, Gujarat, India.
authors.forename: Manoranjan
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Dept. of Pharmacology, Zydus Research Centre, Moraiya, Ahmedabad, Gujarat, India.
authors.forename: Jogeswar
authors.initials: J
authors.lastname: Mohapatra
authors.affiliation: Dept. of Pharmacology, Zydus Research Centre, Moraiya, Ahmedabad, Gujarat, India.
authors.forename: Akshaya
authors.initials: A
authors.lastname: Wagh
authors.affiliation: Dept. of Pharmacology, Zydus Research Centre, Moraiya, Ahmedabad, Gujarat, India.
authors.forename: Hiren M
authors.initials: HM
authors.lastname: Patel
authors.affiliation: Dept. of Pharmacology, Zydus Research Centre, Moraiya, Ahmedabad, Gujarat, India.
authors.forename: Dheerendra
authors.initials: D
authors.lastname: Pandey
authors.affiliation: Dept. of Pharmacology, Zydus Research Centre, Moraiya, Ahmedabad, Gujarat, India.
authors.forename: Shekhar
authors.initials: S
authors.lastname: Kadam
authors.affiliation: Dept. of Medicinal Chemistry, Zydus Research Centre, Moraiya, Ahmedabad, Gujarat, India.
authors.forename: Anil
authors.initials: A
authors.lastname: Argade
authors.affiliation: Dept. of Pharmacology, K.B. Institute of Pharmaceutical Education and Research, Gandhinagar, Gujarat, India.
authors.forename: Shrikalp S
authors.initials: SS
authors.lastname: Deshpande
authors.affiliation: Dept. of Pharmacology, K.B. Institute of Pharmaceutical Education and Research, Gandhinagar, Gujarat, India.
authors.forename: Gourang B
authors.initials: GB
authors.lastname: Shah
authors.affiliation: Dept. of Pharmacology, Zydus Research Centre, Moraiya, Ahmedabad, Gujarat, India. Electronic address: abhijitchatterjee@zyduscadila.com.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Dept. of Pharmacology, Zydus Research Centre, Moraiya, Ahmedabad, Gujarat, India.
authors.forename: Mukul R
authors.initials: MR
authors.lastname: Jain
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072198:ADAM17 Protein; D000208:Acute Disease; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism
chemical_list: D016207:Cytokines; D013267:Stilbenes; D019717:Tissue Inhibitor of Metalloproteinase-3; D016264:Dextran Sulfate; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol
keywords: Inflammatory bowel disease; SIRT-1; TNF-α; TNF-α converting enzyme