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STAT3 regulates endothelial permeability downstream of the pro‐inflammatory cytokines IL6 and TNF‐α
Author(s) -
Alsaffar Hiba,
Martino Nina,
Vincent Peter,
Adam Alejandro,
Lowery Anthony
Publication year - 2016
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.30.1_supplement.165.6
Subject(s) - stat protein , microbiology and biotechnology , stat3 , phosphorylation , tumor necrosis factor alpha , chemistry , kinase , endothelial stem cell , biology , immunology , biochemistry , in vitro
The barrier function of endothelial cells (ECs) is regulated by the action of pro‐inflammatory cytokines. In human dermal microvascular endothelial cells (HDMECs), TNF‐α can induce loss of barrier function in a dose‐dependent manner. Similarly, IL6 can increase endothelial permeability in HDMECs in the presence of its soluble receptor, sIL6Rα. Activation of Src family kinases (SFKs) rendered ECs susceptible to permeability changes in response to a very low dose of TNF‐α. Correspondingly, SFK activation promoted IL6‐induced loss of trans‐endothelial electrical resistance (TEER) even in the absence of its soluble receptor. This loss of permeability in HDMEC correlated with sustained phosphorylation/activation of the signal transducer and activator of transcription (STAT3), as well as an increase in the mRNA expression of its downstream target SOCS3. siRNA‐mediated STAT3 gene knockdown prevented the increase in endothelial permeability in response to treatment of TNF‐α or IL6 with SFK activation. Consistently, pretreatment of HDMECs with ruxolitinib, a JAK kinases inhibitor, blocked STAT3 activation and the increase in permeability in response to TNF‐α or IL6 in the presence of active SFKs. Based on our findings, we conclude that STAT3 activity mediates the change in endothelial monolayer permeability in response to the pro‐inflammatory cytokines TNF‐α and IL6. Support or Funding Information Supported by an AHA SDG grant 13SDG17100110 to APA