Abstract
The inflammasome is a large, multiprotein complex that consists of a nucleotide-binding oligomerization domain-like receptor (NLR), an apoptosis-associated speck-like protein containing a caspase recruitment domain, and pro-caspase-1. Activation of the inflammasome results in cleavage of pro-caspase-1 into cleaved caspase-1, which promotes the processing of pro-interleukin (IL)-1β into mature IL-1β. We investigated the effects of colchicine on non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal injury and activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. Colchicine treatment inhibited indomethacin-induced small intestinal injury by 86% (1 mg/kg) and 94% (3 mg/kg) as indicated by the lesion index 24 h after indomethacin administration. Colchicine inhibited the protein expression of cleaved caspase-1 and mature IL-1β, without affecting the mRNA expression of NLRP3 and IL-1β. Although treatment with recombinant IL-1β (0.1 μg/kg) did not change the severity of small intestinal damage, the preventive effects of colchicine were abolished by supplementation with the same dose of recombinant IL-1β. Indomethacin-induced small intestinal damage was reduced by 77%, as determined by the lesion index in NLRP3−/− mice, and colchicine treatment failed to inhibit small intestinal damage in NLRP3−/− mice. These results demonstrate that colchicine prevents NSAID-induced small intestinal injury by inhibiting activation of the NLRP3 inflammasome.
Highlights
The inflammasome is a large, multiprotein complex that consists of a nucleotide-binding oligomerization domain-like receptor (NLR), an apoptosis-associated speck-like protein containing a caspase recruitment domain, and pro-caspase-1
As we have previously reported that the NLR family pyrin domain-containing 3 (NLRP3) inflammasome plays a crucial role in non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal damage[23], we examined the time-course for changes in NLRP3 and the other inflammasome components during the development of indomethacin-induced small intestinal damage using quantitative real-time RT-PCR
We examined the effect of colchicine treatment on NSAID-induced small intestinal injury and demonstrated that colchicine treatment prevented injury by inhibiting the activation of the NLRP3 inflammasome
Summary
The inflammasome is a large, multiprotein complex that consists of a nucleotide-binding oligomerization domain-like receptor (NLR), an apoptosis-associated speck-like protein containing a caspase recruitment domain, and pro-caspase-1. Indomethacininduced small intestinal damage was reduced by 77%, as determined by the lesion index in NLRP3−/− mice, and colchicine treatment failed to inhibit small intestinal damage in NLRP3−/− mice These results demonstrate that colchicine prevents NSAID-induced small intestinal injury by inhibiting activation of the NLRP3 inflammasome. High mobility group box 1, a nuclear protein regulating gene transcription, is released from injured epithelial cells and binds to TLR4, resulting in nuclear factor-κB (NF-κB) activation through the myeloid differentiation primary-response 88-dependent pathway. This induces the expression of multiple inflammatory cytokines including tumor necrosis factor (TNF)-α, and leads to small intestinal injury[21,22]
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