Background: IL-33 is a member of the IL-1 family whichresides in the nucleus and binds chromatin. IL-33 is released from necrotic, but not apoptotic, cells in response to cell injury or infection, acting as an endogenous “alarmin”. IL-33 binds to its receptor (ST2) on immune cells causing the release of IL-5 and IL-13 via NF-kB and MAPKs. IL-33 may also have a protective role in terms of endothelial integrity and function in the pathogenesis of pulmonary arterial hypertension (PAH). Method and results: siRNA knockdown of IL-33 in human pulmonary arterial endothelial cells resulted in a 1.8±0.22-, 1.3±0.13- and 1.4±0.20-fold increase in IL-6, BMP-9 and ST2 mRNA, respectively; whereas CCL5, CX3CL1 and cathepsin-L mRNA was decreased by 1.5±0.03-, 1.7±0.01- and 2.1±0.17-fold respectively (n=3). Chromatin immunoprecipitation demonstrated that IL-33 bound multiple putative homeodomain protein binding motifs in the proximal and distal promoters of these genes. There was a significant increase in soluble (s)ST2 in the serum of patients with idiopathic PAH, compared to healthy controls: in contrast, there was no significant change in serum IL-33. There was also a significant increase in sST2 in the supernatant of human lung microvascular endothelial cells from patients with IPAH compared to that from control cells. IL-33 was not detectable. Conclusion : IL-33 regulates the expression of IL-6 and sST2, an endogenous IL-33 inhibitor, and may play an important role in the pathogenesis of PAH. Funded by: The Doverdale Trust, Royal Brompton Hospital, London, UK.
Shao et al. (Mon,) studied this question.
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