title: Hypertonic stress regulates T cell function via pannexin-1 hemichannels and P2X receptors.
abstract: Hypertonic saline (HS) resuscitation increases T cell function and inhibits posttraumatic T cell anergy, which can reduce immunosuppression and sepsis in trauma patients. We have previously shown that HS induces the release of cellular ATP and enhances T cell function. However, the mechanism by which HS induces ATP release and the subsequent regulation of T cell function by ATP remain poorly understood. In the present study, we show that inhibition of the gap junction hemichannel pannexin-1 (Panx1) blocks ATP release in response to HS, and HS exposure triggers significant changes in the expression of all P2X-type ATP receptors in Jurkat T cells. Blocking or silencing of Panx1 or of P2X1, P2X4, or P2X7 receptors blunts HS-induced p38 MAPK activation and the stimulatory effects of HS on TCR/CD28-induced IL-2 gene transcription. Moreover, treatment with HS or agonists of P2X receptors overcomes T cell suppression induced by the anti-inflammatory cytokine IL-10. These findings indicate that Panx1 hemichannels facilitate ATP release in response to hypertonic stress and that P2X1, P2X4, and P2X7 receptor activation enhances T cell function. We conclude that HS and P2 receptor agonists promote T cell function and thus, could be used to improve T cell function in trauma patients.
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Woehrle
authors.forename: Linda
authors.initials: L
authors.lastname: Yip
authors.forename: Monali
authors.initials: M
authors.lastname: Manohar
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sumi
authors.forename: Yongli
authors.initials: Y
authors.lastname: Yao
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Junger
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017630:Connexins / Q000502:physiology*; D005682:Gadolinium / Q000494:pharmacology; D006801:Humans; D016753:Interleukin-10 / Q000502:physiology; D007376:Interleukin-2 / Q000235:genetics; D019169:Jurkat Cells; D009419:Nerve Tissue Proteins / Q000502:physiology*; D058469:Receptors, Purinergic P2X / Q000502:physiology*; D058474:Receptors, Purinergic P2X1 / Q000502:physiology; D058848:Receptors, Purinergic P2X4 / Q000502:physiology; D058486:Receptors, Purinergic P2X7 / Q000502:physiology; D012462:Saline Solution, Hypertonic / Q000494:pharmacology*; D013312:Stress, Physiological / Q000276:immunology*; D013601:T-Lymphocytes / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017630:Connexins; D007376:Interleukin-2; D009419:Nerve Tissue Proteins; C492764:PANX1 protein, human; D058469:Receptors, Purinergic P2X; D058474:Receptors, Purinergic P2X1; D058848:Receptors, Purinergic P2X4; D058486:Receptors, Purinergic P2X7; D012462:Saline Solution, Hypertonic; D016753:Interleukin-10; D000255:Adenosine Triphosphate; D005682:Gadolinium; D048051:p38 Mitogen-Activated Protein Kinases; C038958:gadolinium chloride