ADAM33 Connection to the Asthma inflammatory pathway.
Asthma is caused by inflammation in the airways. Inflammation is a protective response to an infection by the immune system that requires communication between different classes of immune cells to coordinate their actions. In sensitive people, asthma conditions can be triggered by hyperactive response of the inflammation pathway. Secreted cytokine proteins provide signals between immune cells to coordinate the inflammatory response. Using String and Biocarta I was able to make observations of the role of ADAM33 in asthma.
String: Interactions between ADAM33 proteins.
Analysis
The following proteins above were found to be connected using STRINGS automated text mining. Text mining scans journal articles mentioned in PubMed to create an interaction network of proteins. ILI3 is a protein that inhibits cytokine production. It synthesizes with IL2 in regulating interferon-gamma synthesis and may be critical in regulating inflammatory and immune responses [4]. Linkage analysis has mapped susceptibility to asthma to a region on human chromosome 5q25-31, which includes the genes for IL-13 and IL4R [5]. String does not include specific information on how the proteins interact so further research would need to be done to determine if SNP effects activation of ADAM33 from IL13.
Another important interaction to note is the pathway of the IL4 protein and ADAM33. The IL-4 protein is involved in the cytokine response pathway. This is an important pathway in determining a persons response to environmental factors. In asthmatic patients a hyperactive response to environmental factors leads to constricted airflow. The Il-4 protein activates IL4R which binds to the IL13 protein activates ADAM33. The role of ADAM33 mutations in asthma developments is unclear, but this gives interesting implications to the role of ADAM33 in the cytokine response pathway.
Another important interaction to note is the pathway of the IL4 protein and ADAM33. The IL-4 protein is involved in the cytokine response pathway. This is an important pathway in determining a persons response to environmental factors. In asthmatic patients a hyperactive response to environmental factors leads to constricted airflow. The Il-4 protein activates IL4R which binds to the IL13 protein activates ADAM33. The role of ADAM33 mutations in asthma developments is unclear, but this gives interesting implications to the role of ADAM33 in the cytokine response pathway.
BioCarta: Inflammatory response pathway.
Analysis of figure:
Shown above is the pathway of cytokine response. Some cytokines such as Il-1 and TNF act to broadly provoke the inflammatory response, while others act on specific type of immune cells. IL-2 is a key mediator of T cell proliferation and activation. T helper cells induce clonal expansion of T cells that respond to antigens. Both Il-4 and Il-2 were shown to have indirect interactions with the ADAM33 protein. Mutations in ADAM33 may be working to promote a hyper-reactive response in lung endothelial cells and fibroblasts or effect the inhibition of IL-2 proteins. [1]
More detail of the pathways can be seen here: IL-2 Pathway, Il-4 Pathway
More detail of the pathways can be seen here: IL-2 Pathway, Il-4 Pathway
TH2 Pathway
Figure: Wikipedia- http://en.wikipedia.org/wiki/File:Lymphocyte_activation.png
Analysis
It is the influence of IL-4 and IL-13 that leads to proliferation TH2 cells that appear to be required for expression of the asthma phenotype. Importantly, the combined action of IL-4, IL-13, CD40, and an enzyme called activation-induced cytidine deaminase induces deletional switch recombination in B lymphocytes and the production of allergen-specific IgE, levels of which are increased in atopic asthma. ADAM33 has been associated with IL-4 and IL-13 proteins and may have an effect on that pathway. It is the ability of IgE to specifically bind allergen and receptors on the effector cells of the allergic response, including mast cells, basophils, and eosinophils, that allows release of the mediators that cause asthma symptoms. [3]
References:
- Biocarta - Charting Pathway. http://www.biocarta.com/pathfiles/h_inflamPathway.asp
- http://string.embl.de/newstring_cgi/show_network_section.pl?taskId=OHpzbMruzooE&interactive=yes&network_flavor=action
- Craig M. Lilly Diversity of asthma: Evolving concepts of pathophysiology and lessons from genetics. The Journal of Allergy and Clinical Immunology
Volume 115, Issue 4, Supplement , Pages S526-S531, April 2005 - Genecard http://www.genecards.org/cgi-bin/carddisp.pl?gene=IL13
- Grunig, G., Warnock, M., et al., Requirement for IL-13 Independently of IL-4 in Experimental Asthma. Science 18 December 1998:
Vol. 282 no. 5397 pp. 2261-2263