The calpain inhibitor was added to the culture at final concentrations described previously

recognised by pattern recognition receptors located both on the cell surface, as well as intracellularly ). Three common variants of the NLR gene caspase activation and recruitment domain 15 ) has been associated with CD: SNP 8, 12 and 13. CARD15 recognises the PAMP muramyl dipeptide, which is a peptidoglycan constituent of the cell wall of both gram-negative and grampositive bacteria and is the minimal motif recognised by CARD15. Interaction between MDP and CARD15 leads to activation of the nuclear factor kB by binding of the LJH685 adaptor protein RIP2 to CARD15 via caspase recruitment domains on both proteins. RIP2 activates NFkB both by down-regulation of the NFkB inhibitor, IkBa, and by activation of the TAK1 kinase and the IkB Kinase complex. NFkB subsequently translocates into the nucleus, where it acts as a transcription factor for pro-inflammatory mediators, including the PF-04979064 cytokines tumour necrosis factor-a and interleukin-1b. CARD15 stimulation also leads to activation of the mitogen-activated protein kinases, p38 and JNK, through binding of CARD9 to CARD15. TAK1 has also been proposed to be an upstream activator of MAP kinases. MDP is also able to activate a pro-inflammatory response directly, i.e. by activating the inflammasome, which in turn activates the pro-inflammatory caspase 1 enzyme that cleaves the pro-inflammatory cytokines IL-1b and IL-18 leading to their activation. MDP bind to NALP3 thereby facilitating binding to ASC by a pyrin domain -PYD interaction. ASC contains a CARD domain that recruits pro-caspase 1, which is subsequently cleaved and activated. NALP1 has recently been shown to possess a similar ability to sense MDP directly and interestingly MDP activated CARD15 also activates NALP1. Activated caspase 1 and IL-1b has been shown to be co-secreted into the extracellular space. The role of CARD15 in the pathogenesis of CD is still debated. A number of studies have shown that the CARD15 variants associated with CD cause impaired NFkB activation of peripheral mononuclear cells. However, other studies have shown a gain-of-function phenotype for these mutations in monocytes isolated from CARD15 mutated mice. A recent study has shown that mono

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