title: Norepinephrine and adenosine-5'-triphosphate synergize in inducing IL-6 production by human dermal microvascular endothelial cells.
abstract: Endothelial cells (ECs) play important roles in cutaneous inflammation, in part, by release of inflammatory chemokines/cytokines. Because dermal blood vessels are innervated by sympathetic nerves, the sympathetic neurotransmitter norepinephrine (NE) and the co-transmitter adenosine-5'-triphosphate (ATP) may regulate expression of EC inflammatory factors. We focused on IL-6 regulation because it has many inflammatory and immune functions, including participation in Th17 cell differentiation. Strikingly, NE and ATP synergistically induced release of IL-6 by a human dermal microvascular endothelial cell line (HMEC-1). Adrenergic antagonist and agonist studies indicated that the effect of NE on induced IL-6 release is primarily mediated by β2-adrenergic receptors (ARs). By real-time PCR IL-6 mRNA was also synergistically induced in HMEC-1 cells. This synergistic effect of NE and ATP was reproduced in primary human dermal endothelial cells (pHDMECs) and is also primarily mediated by β2-ARs. Under conditions of stress, activation of the symphathetic nervous system may lead to release of ATP and NE by sympathetic nerves surrounding dermal blood vessels with induction of IL-6 production by ECs. IL-6 may then participate in immune and inflammatory processes including generation of Th17 cells. Production of IL-6 in this manner might explain stress-induced exacerbation of psoriasis, and perhaps, other skin disorders involving Th17-type immunity.
authors.affiliation: Department of Dermatology, Weill Cornell Medical College, 1305 York Avenue, 9th Floor, New York, NY 10021, United States.
authors.forename: Lori L
authors.initials: LL
authors.lastname: Stohl
authors.forename: Julie B
authors.initials: JB
authors.lastname: Zang
authors.forename: Wanhong
authors.initials: W
authors.lastname: Ding
authors.forename: Michela
authors.initials: M
authors.lastname: Manni
authors.forename: Xi K
authors.initials: XK
authors.lastname: Zhou
authors.forename: Richard D
authors.initials: RD
authors.lastname: Granstein
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D058672:Adrenergic beta-2 Receptor Antagonists; D002452:Cell Count; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D020405:Dermis / Q000166:cytology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D055806:Microvessels / Q000166:cytology*; D009638:Norepinephrine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; C508600:IL6 protein, human; D015850:Interleukin-6; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D000255:Adenosine Triphosphate; D009638:Norepinephrine
keywords: AR; ATP; Adenosine-5′-triphosphate; DM; EC; Endothelial cells; ICAM-1; IL-6; NE; Norepinephrine; Prop; SNS; Sal; adenosine-5′-triphosphate; adrenergic receptor; depleted medium; endothelial cell; intercellular adhesion molecule 1; norepinephrine; pHDMEC; primary human dermal endothelial cells; propranolol; salbutamol; sympathetic nervous system
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