Friday, 23 September 2011

Interleukin-33


Interleukin-33, a member of the IL-1 family of cytokines, is expressed by many cell types following pro-inflammatory stimulation and is thought to be released on cell lysis. The predicted 270-amino acid human pro-IL-33 has a calculated molecular mass of 30 kDa. Whether pro-IL-33 needs to be cleaved to be active and whether caspase-1 is required is still a matter of controversy. However, it has been reported that IL-33 is biologically active in a caspase-1 independent manner. The heterodimeric IL-33 receptor complex consists of ST2 and IL-1 receptor accessory protein (IL-1rAp) and mediates signaling through the TLR domain of IL-1rAp.



Binding of IL-33 to its receptor results in the recruitment of myD88, IRAK1, and IRAK4 to the receptor complex, activating NF-κb, Iκbα and numerous MAPKs. Cell-specific variations in the IL-33 induced signaling pathway have been described, such as the requirement of TRAF6 for IRAK recruitment in fibroblasts. In addition, IL-33 may function as a transcriptional repressor mediated by the N-terminal homeobox domain. Soluble ST2 can bind IL-33 directly and acts as a decoy receptor. Taken together IL-33 may be a dual function cytokine with both extracellular and intracellular signalling, a property it shares with IL-1α.

IL-33 affects the various cell types that express membrane ST2. ST2 is selectively expressed by TH2 but not TH1 cells. IL-33 is described as a modulator of inflammation, mediating TH2 immune responses. Administration of purified IL-33 in vitro and in vivo induces TH2-associated cytokines such as IL-5 and IL-13 and reduces production of IFN-γ from TH1 cells. IL-33 is a potent inducer of pro-inflammatory cytokines and chemokines.

The ability of IL-33 to target numerous immune cell types, like TH2-like cells, mast cells and B1 cells, and to induce cytokine and chemokine production underlines its potential in influencing the outcome of wide range of diseases such as:
  • Arthritis
  • Asthma
  • Atopic Allergy and Anaphylaxis
  • Cardiovascular Diseases / Atherosclerosis
  • Nervous System Diseases
  • Sepsis

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