Both innate and adaptive immune responses contribute to the onset of mucosal inflammation in CD patients [1]. Fragments of selleck chemicals llc gliadin �C a major group of proteins in gluten �C cross the epithelium, and are presented by antigen presenting cells to the HLA-DQ2 or HLA-DQ8-restricted CD4+ ��/�� T lymphocytes present in jejunal mucosa [2]. Recently, other nongluten components of wheat (amylase inhibitors) were reported to contribute to the specific response by stimulation of innate immunity cells [3]. The activated gliadin-specific T lymphocytes produce a spectrum of mediators and cytokines of a Th1 profile, mainly IFN-��. These mechanisms could participate in intestinal tissue damage by contributing to the proinflammatory environment in the tissue and by activating tissue enzymes, including metalloproteases and tissue transglutaminase [4].

Besides IFN-��, other cytokines such as IL-1��, IL-6, IL-15, IL-23 and TNF-�� produced by innate immune cells contribute to the ongoing inflammation in CD [5]�C[7]. IL-1�� that belongs to the IL-1 cytokine family together with IL-1��, IL-18, and IL-33, has been associated with the inflammatory conditions in CD patients, and was shown to control the secretion of IL-23 leading to a shift to the Th1/Th17 immune pathway [7]�C[9]. Production of IL-1�� from inflammatory cells such as monocytes and macrophages requires the following steps: the expression of the pro-IL-1�� gene and the synthesis of immature pro-IL-1�� protein; the cleavage of pro-IL-1�� by active caspase-1 to yield the mature form of IL-1��; and the secretion of mature IL-1�� from the cells.

The generation of mature IL-1�� is tightly controlled by a diverse class of cytosolic protein complexes, known as inflammasomes. Several different inflammasomes have been described, of which NLRP3 and NLRP1 (Nod-like receptor family, containing pyrin domain 3 and 1) inflammasomes have been the most intensively studied. GSK-3 Upon sensing danger signals, the NLRP3 proteins oligomerize and recruit caspase-1 through the adaptor protein apoptosis-associated speck like protein (ASC). Subsequently, caspase-1 undergoes an autocatalytic activation that involves the autoproteolytic processing of the 45-kDa pro-caspase-1 into 20- and 10-kDa subunits. In turn, mature caspase-1 cleaves pro-IL-1��, producing mature IL-1�� [10]. In macrophages and dendritic cells (DCs), two temporally separate signals are required to yield the active proinflammatory cytokine. The first signal involves the activation of pattern recognition receptors [e.g. Toll like receptors (TLRs) or Nucleotide Oligomerization Domain (NOD)-like receptors] by pathogen- and danger-associated molecular patterns, which triggers the expression of pro-IL-1�� via the NF-��B pathway [11]. Then microbial products [e.g.