BACKGROUND: The Kv1.3 voltage-gated potassium channel is selectively upregulated upon activation in effector memory T (TEM ) cells in inflamed tissue, and plays an important role in maintenance of T-cell activation. Although Kv1.3 blockers have been shown to ameliorate allergic contact dermatitis (ACD) in a rat model, it remains unknown whether the effect of Kv1.3 blockers on ACD is mediated by suppressing TEM cell function and/or whether naive T-cells or central memory T (TCM ) cells are influenced. AIM: To analyse the detailed mechanism of Kv1.3 blockers in a rat model of ACD. METHODS: We examined the effects of a Kv1.3 blocker on inflammation and production of the effector cytokine interferon (IFN)-γ in inflamed tissue in rat ACD. Single-cell suspensions were isolated from inflamed rat ears (TEM cells), and regional lymph nodes (naive T/TCM cells), and the effect of Kv1.3 blockers on anti-CD3-stimulated IFN-γ production in vitro was measured. RESULTS: The Kv1.3 blocker significantly suppressed ear inflammation and IFN-γ production at the protein level in vivo. It also suppressed in vitro IFN-γ production from TEM cells from inflamed tissues, but did not suppress the function of naive T/TCM cells from lymph nodes. CONCLUSIONS: We found that the Kv1.3 blocker ameliorated ACD by inhibiting TEM cell functions only, thus Kv1.3 blockers could be a potentially selective therapeutic agent for TEM cell-mediated inflammatory skin diseases without producing harmful side-effects.
BACKGROUND: The Kv1.3 voltage-gated potassium channel is selectively upregulated upon activation in effector memory T (TEM ) cells in inflamed tissue, and plays an important role in maintenance of T-cell activation. Although Kv1.3 blockers have been shown to ameliorate allergic contact dermatitis (ACD) in a rat model, it remains unknown whether the effect of Kv1.3 blockers on ACD is mediated by suppressing TEM cell function and/or whether naive T-cells or central memory T (TCM ) cells are influenced. AIM: To analyse the detailed mechanism of Kv1.3 blockers in a rat model of ACD. METHODS: We examined the effects of a Kv1.3 blocker on inflammation and production of the effector cytokine interferon (IFN)-γ in inflamed tissue in rat ACD. Single-cell suspensions were isolated from inflamed rat ears (TEM cells), and regional lymph nodes (naive T/TCM cells), and the effect of Kv1.3 blockers on anti-CD3-stimulated IFN-γ production in vitro was measured. RESULTS: The Kv1.3 blocker significantly suppressed ear inflammation and IFN-γ production at the protein level in vivo. It also suppressed in vitro IFN-γ production from TEM cells from inflamed tissues, but did not suppress the function of naive T/TCM cells from lymph nodes. CONCLUSIONS: We found that the Kv1.3 blocker ameliorated ACD by inhibiting TEM cell functions only, thus Kv1.3 blockers could be a potentially selective therapeutic agent for TEM cell-mediated inflammatory skin diseases without producing harmful side-effects.
Authors: Seow Theng Ong; Saumya Bajaj; Mark R Tanner; Shih Chieh Chang; Bankala Krishnarjuna; Xuan Rui Ng; Rodrigo A V Morales; Ming Wei Chen; Dahai Luo; Dharmeshkumar Patel; Sabina Yasmin; Jeremy Jun Heng Ng; Zhong Zhuang; Hai M Nguyen; Abbas El Sahili; Julien Lescar; Rahul Patil; Susan A Charman; Edward G Robins; Julian L Goggi; Peng Wen Tan; Pragalath Sadasivam; Boominathan Ramasamy; Siddana V Hartimath; Vikas Dhawan; Janna Bednenko; Paul Colussi; Heike Wulff; Michael W Pennington; Serdar Kuyucak; Raymond S Norton; Christine Beeton; K George Chandy Journal: ACS Pharmacol Transl Sci Date: 2020-05-14
Authors: Manuela B Pucca; Thaís B Bertolini; Felipe A Cerni; Karla C F Bordon; Steve Peigneur; Jan Tytgat; Vânia L Bonato; Eliane C Arantes Journal: Immunology Date: 2016-02 Impact factor: 7.397
Authors: Eugene Y Chiang; Tianbo Li; Surinder Jeet; Ivan Peng; Juan Zhang; Wyne P Lee; Jason DeVoss; Patrick Caplazi; Jun Chen; Søren Warming; David H Hackos; Susmith Mukund; Christopher M Koth; Jane L Grogan Journal: Nat Commun Date: 2017-03-01 Impact factor: 14.919