The role of Inositol 1,4,5 triphosphate kinase C in the pathogenesis of Kawasaki disease
Pediatric Rheumatology volume 9, Article number: P295 (2011)
Kawasaki disease (KD) is a childhood multisystemic vasculitis resulting in the development of coronary aneurysms. Functional polymorphism in Inositol 1,4,5-triphosphate kinase C (ITPKC) has recently been identified and linked to KD susceptibility and severity. ITPKC acts as a negative regulator of T-cell activation through the inhibition of Ca2+/Nuclear factor of activated T-cells (NFAT) signalling pathway. Lactobacillus casei cell wall extract induced coronary arteritis is an animal model of KD dependent on superantigenic activity.
To determine the role of ITPKC in the pathogenesis of KD.
To assess the role of ITPKC in lymphocyte activation, mouse splenocytes were stimulated with superantigen and T-cell proliferation, cytokines production, Ca2+ flux and ITPKC protein expression were measured by 3H thymidine, ELISA, flow cytometry, and Western blot, respectively. To confirm the results in a human system, lymphocyte activation was determined in a human cell line after siRNA knockdown.
ITPKC was upregulated at both mRNA and protein levels by mouse splenocytes following superantigen stimulation. Cyclosporin A inhibition of Ca2+/NFAT signalling abolished T-cell proliferation and cytokine production following superantigen activation. ITPKC knockdown in superantigen activated human lymphocyte cell line could not completely inhibit cytokine production or Ca2+ flux.
Although ITPKC and the Ca2+/NFAT signalling pathway were activated in lymphocytes following superantigen stimulation, inhibition of ITPKC was not able to alter lymphocyte activation or Ca2+ flux pointing to overlapping or compensatory pathways. These findings may account for the conflicting reports on the association between ITPKC polymorphisms and KD in different ethnicities.
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Khajoee, V., Yeung, R.S. The role of Inositol 1,4,5 triphosphate kinase C in the pathogenesis of Kawasaki disease. Pediatr Rheumatol 9 (Suppl 1), P295 (2011). https://doi.org/10.1186/1546-0096-9-S1-P295