This pattern of activation of MAPK pathways is similar to what previously have been found in whole intestinal biopsies from patients with active IBD. Although the response seems to be normal, it is interesting that it is seen in CARD15 mutated monocytes here. The finding suggests that MDP dependent activation of p38 occurs through other MDP sensing PRRs in human monocytes. It is, however, also reassuring that p38 is activated by MDP in CD monocytes, as it confirms that control and CD cells have been stimulated. It is unlikely that the stimulation could be due to TLR2 dependent signalling, since MDP alone has not been shown to activate TLR2. The results reveal an impairment of a specific NLR pathway in CD monocytes not carrying the disease associated CARD15 variants, and therefore add evidence to the theory of a dysfunctional innate immune response in CD monocytes. It also emphasises that studies into the role of the NLR pathway in CD monocytes should employ CARD15 nonmutated CD monocytes as well as CARD15 EL-102 non-mutated control monocytes, since non-mutated CARD15 monocytes from CD patients also appear to have dysfunctional PRR pathways. From animal experimental studies there is increasing evidence of how MDP-signalling seem to protect from inflammatory bowel disease. Chronic MDP-stimulation thus seem to downregulate signalling through other PRRs and protect mice from colitis. Whether similar effects are to be found in human remain to be investigated. In order to map the other possible consequences of MDP stimulation of monocytes, the present study examined the effect of MDP on inflammasome molecule expression and activation. It was shown that caspase 1 expression on the mRNA level is positively regulated by MDP stimulation, whereas NALP3 expression is unaltered. This has not previously been described. Interestingly, this caspase 1-mRNA upregulation was inhibited in CD CARD15 non-mutated monocytes, which further substantiates a decreased MDP response in CD monocytes. In this experimental setting MDP did not activate the inflammasome as evidenced by a lack of caspase 1 RSL3 (1S,3R-) cleavage. Thus, we found a constitutive activation of the inflammasome in CD monocytes regardless of the CARD15 status. This might contrib
