title: Elevated levels of mast cells are involved in pruritus associated with polycythemia vera in JAK2V617F transgenic mice.
abstract: Pruritus occurs frequently in patients with polycythemia vera (PV), and the pathophysiology of PV-associated pruritus is unclear. We have previously demonstrated that transgenic mice expressing JAK2V617F displayed clear PV-like phenotypes. In the current study, we found frequent occurrence of pruritus with aged JAK2V617F transgenic mice and further investigated the underlying mechanisms by studying mast cells, key players in allergic reactions and anaphylaxis. Massive accumulations of mast cells were observed in the skin of pruritic JAK2V617F transgenic mice. In vitro culture yielded much higher mast cell counts from the bone marrow, spleen, peripheral blood, and peritoneal cavity of JAK2V617F transgenic mice than from controls. Cultured mast cells from JAK2V617F transgenic mice exhibited enhanced proliferative signals, relative resistance to cell death upon growth factor deprivation, and a growth advantage over control cells under suboptimal growth conditions. However, these mast cells displayed normal morphology and contained normal levels of mast cell proteases before and after degranulation. Finally, the JAK2 inhibitor G6 effectively reduced mast cell numbers and alleviated pruritus in JAK2V617F transgenic mice. Collectively, these data demonstrate that mast cells are involved in PV-associated pruritogenesis and that JAK2 inhibitors are potential antipruritus drugs.
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; and.
authors.forename: Xi
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; and.
authors.forename: Wanke
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32611.
authors.forename: Annet
authors.initials: A
authors.lastname: Kirabo
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32611.
authors.forename: Sung O
authors.initials: SO
authors.lastname: Park
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; and.
authors.forename: Wanting T
authors.initials: WT
authors.lastname: Ho
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32611.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Sayeski
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; and joe-zhao@ouhsc.edu.
authors.forename: Zhizhuang J
authors.initials: ZJ
authors.lastname: Zhao
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008407:Mast Cells / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011087:Polycythemia Vera / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011537:Pruritus / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D012867:Skin / Q000378:metabolism / Q000473:pathology; D019089:Stem Cell Factor / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology; D013997:Time Factors
chemical_list: C576143:G6 stilbenoid tyrosine kinase inhibitor; D007377:Interleukin-3; D047428:Protein Kinase Inhibitors; D019089:Stem Cell Factor; D013267:Stilbenes; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases