Introduction. Asthma is a complex disease associated with airway inflammation, mucus hypersecretion, and bronchoconstriction1. In older literature, asthma was seen as simply an IgE-mast cell mediated response. However, recent studies have had a greater focus on the different endotypes (subtypes) of asthma. This is significant because future treatment can progress from general symptomatic treatment to personalized medication based on the individual’s asthmatic endotype2-3. Progress has been made in observing the different endotypes of asthma, such as rhinovirus induced asthma4, asthma due to single nucleotide polymorphisms5 for myddosome genes, and various others. Though there are different causes of this complex disease, a commonality among them is a mechanism involving interleukin-33/ST2 activation causing for a myddosome complex formed by IRAK-1/IRAK-M/PIN-1 leading to a chronic Th2 environment6-7. Methods. OVA (ovalbumin) mice with chronic inflammation of the lungs mimicking asthma, were utilized to observe how gene knockout of IRAK and PIN1 could reduce downstream activation by IL-337. Researchers compared results of the OVA- IRAK KO mice to wild type and also PBS mice, which were mice with minimal inflammation. Other significant methods included PIN1 activity assay, animal handling and asthma induction, gene expression profiling, pathway and functional analysis, and NMR analysis for IRAK-M-PIN. Results. IRAK-M and PIN-1 KO OVA mice showed significant reductions in IL-6, IL-4, and IL-5 in response to IL-33 while the PBS mice showed no changes. The OVA IRAK KO mice also had a reduction in collagen deposition and mucus production compared to the wild type mice. PBS- IRAK-M KO mice again showed no significant change in Th2. OVA- IRAK-M KO mice on the other hand had reduced Th2 cells and an increase in Th1 cells6. Conclusions. Studies have shown that IL-33/IRAK-1/IRAK-M activation plays a significant role in mediating the excessive production of inflammatory Th2 cytokines. By utilizing IRAK KO mice, researchers were able to see a tremendous decrease in cytokine production. This was able to prevent a predominant Th2 environment, while also increasing Th1 cells which are typically reduced in asthmatics. Furthermore, by reducing Th2, there was less activation of the ST2 (IL-33) receptor, possibly preventing positive feedback of the inflammatory mechanism. By preventing the rise in Th2, there was reduced inflammation within the models which prevented excessive airway remodeling. Overall, the relationship between IL-33 and IRAK-1 must continue to be studied due to its significant involvement in the various endotypes of asthma.
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