IL-6/p-BTK/p-ERK signaling mediates calcium phosphate-induced pruritus

Sunita Keshari, Apriska Dewi Sipayung, Ching Chuan Hsieh, Li Jen Su, Yun Ru Chiang, Huan Cheng Chang, Wu Chang Yang, Tsung Hsien Chuang, Chien Lung Chen, Chun Ming Huang

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16 Scopus citations


Uremic pruritus with elevated levels of calcium phosphate (CaP) in skin is a common symptom in patients with chronic kidney disease (CKD). In this study, we demonstrate that intradermal injection of CaP into mice triggered scratching by up-regulating the IL-6 in skin and phosphorylation of ERKs in dorsal root ganglion (DRG) in a dose-dependent manner. IL-6 is essential because the CaP-induced up-regulation of phosphorylated (p)-ERK in DRG was considerably reduced in the IL-6 knockout mice. Microarray analysis in conjunction with real-time PCR revealed a higher mRNA expression of Bruton's tyrosine kinase (BTK) gene in DRG after CaP injection. The inhibition of BTK by ibrutinib noticeably diminish the CaP-induced up-regulation of IL-6 and p-ERK in mice. A high amount of IL-6 was detected in itchy skin and blood of patients with CKD. The expressions of p-BTK and p-ERK in DRG primary cells reached maximum levels at 1 and 10 min, respectively, after treatment of recombinant IL-6 and were significantly reduced by treatment of IL-6 along with ibrutinib. The mechanism by which the CaP-induced pruritus mediated by the IL-6/p-BTK/p-ERK signaling was revealed.—Keshari, S., Sipayung, A. D., Hsieh, C.-C., Su, L.-J., Chiang, Y.-R., Chang, H.-C., Yang, W.-C., Chuang, T.-H., Chen, C.-L., Huang, C.-M. IL-6/p-BTK/p-ERK signaling mediates calcium phosphate-induced pruritus. FASEB J. 33, 12036-12046 (2019).

Original languageEnglish
Pages (from-to)12036-12046
Number of pages11
JournalFASEB Journal
Issue number11
StatePublished - 1 Nov 2019


  • Bruton's tyrosine kinase
  • CKD
  • CaP


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