Cytokine. 2014 Mar;66(1):30-9. doi: 10.1016/j.cyto.2013.12.010. Epub 2014 Jan 4.
Involvement of TACE in colon inflammation: a novel mechanism of regulation via SIRT-1 activation.
Sharma M1, Mohapatra J1, Wagh A1, Patel HM1, Pandey D1, Kadam S1, Argade A2, Deshpande SS3, Shah GB3, Chatterjee A4, Jain MR1.
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.
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.
KEYWORDS:
Inflammatory bowel disease; SIRT-1; TNF-α; TNF-α converting enzyme- PMID:
- 24548422
- DOI:
- 10.1016/j.cyto.2013.12.010
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