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Specific Silencing of Janus Kinases on Proliferating T Lymphocytes
Author(s) -
GómezValadés Alicia,
Llamas Maria,
GómezCasajús Lluís,
Mascaró Cristina
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.lb304
Subject(s) - janus kinase , gene silencing , transfection , janus kinase 3 , kinase , small interfering rna , haematopoiesis , tyrosine kinase 2 , jak stat signaling pathway , rna interference , microbiology and biotechnology , stat , janus kinase 2 , chemistry , biology , signal transduction , cell culture , stat3 , receptor , t cell , rna , immune system , il 2 receptor , immunology , stem cell , receptor tyrosine kinase , gene , growth factor , biochemistry , genetics , platelet derived growth factor receptor
Jak3 is the only janus kinase among the four family members (Jak1. Jak2, Jak3, and Tyk2) which is predominantly expressed in haematopoietic linage. Small molecule inhibitors of the Jak's are being actively studied for immunosuppressive therapies. Nevertheless, they have not shown a selective pattern versus the different family members and implications over the therapeutic efficiency of a JAK3‐specific antagonist remain unclear. In this study we aim to investigate the effects of specific Jak3 inhibition using the powerful and specific iRNA technology. Specific sequences against human Jak1 and Jak3 were designed and successfully transfected into primary human T lymphocytes. Upon siRNA treatment, specific and stable silencing was observed at the RNA and protein level. After selective Jak abrogation, IL‐2‐induced proliferation was potently inhibited, and cell death was clearly induced. These effects on cell viability were dose dependent, in correlation with silencing effect. Nevertheless, we never observed an additive effect over the viability when Jak1 and Jak3 (whose heterodimerization is required to transduce IL‐2 signalling) were co‐silenced. These data indicate that a selective Jak3 inhibitor can, per se, modulate IL‐2 signalling, reinforcing the idea that a Jak3 selective antagonist could report therapeutic benefits as immunosuppressant.