The IL-33-ST2 pathway

IL-33/ST2 signaling pathway, ST2 antibodiesST2 (also known as T1) is a member of the IL-1 receptor family (IL-1R) and comes in at least three isoforms (membrane bound, soluble and a variant ST2). Its been over a decade since ST2 was reported to be selectively and stably expressed on the surface of Th2 cells and that ST2-specific blocking antibodies or soluble ST2 impairs Th2 cell responses, but until 2005, the ST2 ligand was unknown. IL-33 has recently been identified as the ligand for ST2. IL-33 binds a heterodimer receptor complex consisting of ST2 and IL-1R accessory protein (IL-1RAP), which leads to the recruitment of myeloid differentiation primary-response protein 88 (MYD88) complex. Soluble ST2 can also bind IL-33 directly and act as a decoy receptor, inhibiting its binding to membrane-bound ST2 and subsequent signalling.

There is much to be understood about the processing and release of IL-33, however it is known to be mainly expressed on fibroblasts, epithelial cells and endothelial cell and is secreted in damaged tissues. It has the ability to activate cells of both the innate and adaptive immune system indicating it may have an important role in the initiation and perpetuation of inflammation, however depending on the tissue, it can also promote the resolution of inflammatory responses giving it a dual role in various diseases depending on the mechanism underlying the pathogenesis.

ST2 products available from MD Bioproducts:

The following table lists the suggested involvement of IL-33 and ST2 in various diseases. For a more detailed review of IL-33 and ST2, see "Disease-associated functions of IL-33: the new kid in the IL-33 family" published by Liew, FY., Pitman, N.I. and Mcinnes, I.B in Nature Review Immunology (2010). 

Disease Role of IL-33 and ST2
Infection
  • ST2-specific blocking antibody enhanced Leishmania major resistance in mice
  • Administration of IL-33 confers Trichuris muris resistance in mice
Respiratory syncytial virus
  • ST2-specific blocking antibody reduces pulmonary inflammation in mice
Asthma

 

  • IL-33 levels are elevated in clinical and experimental asthma
  • Blocking ST2 or IL-33 attenuates disease in some models
  • Administration of IL-33 exacerbates experimental asthma and induces features of asthma in animals

 

Allergy & Anaphylaxis

 

  • In the presence of IgE, Il-33 induces anaphylactic shock
  • IL-33 causes degranulation of IgE-primed mast cells in the skin
  • Increased expression of IL-33 by skin cells in clinical atopic dermatitis

 

Cardiovascular disease

 

  • Serum ST2 levels increased in myocardial infarction and heart failure
  • Protective effect of IL-33 in experimental heart failure
  • Atherosclerosis in mice attenuated by IL-33 and exacerbated by soluble ST2

 

Central Nervous System Disease

 

  • ST2 and IL-33 detected following subarachnoid hemmorhage
  • IL-33 associated with Alzheimer's disease where expression is increased

 

Pain
  • IL-33 induces cutaneous and articular hypernociception
Arthritis

 

  • IL-33 and ST2 are increased in the synovium in RA
  • Blocking ST2 attenuates collagen-induced arthritis
  • IL-33 exacerbates collagen-induced arthritis