A network map of IL-33 signaling pathway

Abstract

Interleukin-33 (IL-33) is a member of the IL-1 family of cytokines that play a central role in the regulation of immune responses. Its release from epithelial and endothelial cells is mediated by pro-inflammatory cytokines, cell damage and by recognition of pathogen-associated molecular patterns (PAMPs). The activity of IL-33 is mediated by binding to the IL-33 receptor complex (IL-33R) and activation of NF-κB signaling via the classical MyD88/IRAK/TRAF6 module. IL-33 also induces the phosphorylation and activation of ERK1/2, JNK, p38 and PI3K/AKT signaling modules resulting in the production and release of pro-inflammatory cytokines. Aberrant signaling by IL-33 has been implicated in the pathogenesis of several acute and chronic inflammatory diseases, including asthma, atopic dermatitis, rheumatoid arthritis and ulcerative colitis among others. Considering the biomedical importance of IL-33, we developed a pathway resource of signaling events mediated by IL-33/IL-33R in this study. Using data mined from the published literature, we describe an integrated pathway reaction map of IL-33/IL-33R consisting of 681 proteins and 765 reactions. These include information pertaining to 19 physical interaction events, 740 enzyme catalysis events, 6 protein translocation events, 4 activation/inhibition events, 9 transcriptional regulators and 2492 gene regulation events. The pathway map is publicly available through NetPath ( http://www.netpath.org /), a resource of human signaling pathways developed previously by our group. This resource will provide a platform to the scientific community in facilitating identification of novel therapeutic targets for diseases associated with dysregulated IL-33 signaling. Database URL: http://www.netpath.org/pathways?path_id=NetPath_120 .

IL-33 suppresses GSK-3β activation through an ST2-independent MyD88/TRAF6/RIP/PI3K/Akt pathway

“…This indicates that IL-33 activates PI3K prior to activation of Akt. Several avenues of evidence have pointed to a pathway linked to IL-33-induced PI3K activation or Akt activation [ 26 , 27 , 28 , 29 ]. How IL-33 activates PI3K or Akt, however, remained to be elucidated.…”

Epithelial cell–derived cytokines: more than just signaling the alarm

“…IL-33 binds a heteromeric receptor consisting of ST2 and its coreceptor IL-1 receptor accessory protein (IL-1RAcP). Formation of the IL-33/ST2/IL-1RAcP complex results in recruitment of MyD88 and IL-1R-associated kinase (IRAK) to activate a variety of downstream signaling pathways (96). A soluble variant of ST2 (sST2) that lacks the transmembrane domain appears to function as a decoy receptor to negatively regulate IL-33/ST2 signaling (97,98).…”

IL-33 promotes anemia during chronic inflammation by inhibiting differentiation of erythroid progenitors

“…Among the genes strikingly up-regulated by IL-33 were many members of the NF-κB pathway (Fig. 6, B and C), which transmits IL-33 signals in other cell types (Pinto et al, 2018). Members of both canonical and noncanonical pathways were up-regulated ( Fig.…”