β₂‐Adrenergic receptor regulation of human neutrophil function is sexually dimorphic

Abstract

1 While the mechanisms underlying the marked sexual dimorphism in inflammatory diseases are not well understood, the sexually dimorphic sympathoadrenal axis profoundly affects the inflammatory response. We tested whether adrenergic receptor-mediated activation of human neutrophil function is sexually dimorphic, since neutrophils provide the first line of defense in the inflammatory response. 2 There was a marked sexual dimorphism in b 2 -adrenergic receptor binding, using the specific b 2 -adrenergic receptor ligand, [ 3 H]-dihydroalprenolol, with almost three times more binding sites on neutrophils from females (20,87872470) compared to males (733173179). 3 There was also a marked sexual dimorphism in the effects of isoprenaline, a b-adrenergic receptor agonist, which increased nondirected locomotion (chemokinesis) in neutrophils obtained from females, while having no effect on neutrophils from males. 4 Isoprenaline stimulated the release of a chemotactic factor from neutrophils obtained from females, but not from males. This chemotactic factor acts on the G protein-coupled CXC chemokine receptor 2 (CXCR2) chemokine receptor, since an anti-CXCR2 antibody and the selective nonpeptide CXCR2 antagonist SB225002, inhibited chemotaxis produced by this factor. While interleukin-(IL-) 8 is a principal CXCR2 ligand, isoprenaline did not produce an increase in IL-8 release from neutrophils. 5 IL-8-induced chemotaxis was inhibited in a sexually dimorphic manner by isoprenaline, which also stimulated release of a mediator from neutrophils that induced chemotaxis, that was inhibited by anti-CXCR2 antibodies. 6 These findings indicate an important role for adrenergic receptors in the modulation of neutrophil trafficking, which could contribute to sex-differences in the inflammatory response.

Interleukin-8: novel roles in human airway smooth muscle cell contraction and migration

“…To analyze messenger RNA (mRNA), we synthesized single-strand cDNA in a 20-l reaction mixture using 2 g of total RNA as a template, oligo(dT) [12][13][14][15][16][17][18] primer, and Superscript II enzyme in the presence of acetylated BSA (GIBCO BRL) and RNAguard ribonuclease inhibitor (Pharmacia Biotech, Quebec, Canada). PCR reactions were performed (Light Cycler; Roche Molecular Biochemicals) with 20 l of reaction mixture containing 2 l of cDNA, 4 l of both sense and antisense primers for CXCR1 and CXCR2 (CXCR1: sense, 5Ј-ATGTCAAATATTACAGATCC, antisense, 3Ј-AGATTCATAGACAGTCCCCA; CXCR2: sense, 5Ј-GAGGAC-CCAGGTGATCCAGG, antisense, 3Ј-GAGAGTAGTGGAAGTGT-GCC) or housekeeping gene (␤-actin), 1.6 l of MgCl 2 (3 mM), and 2 l of fast-start DNA SYBR green with Taq polymerase.…”

β2-Adrenergic receptor-dependent sexual dimorphism for murine leukocyte migration

“…Stimulation of the β 2 -adrenergic receptor has been shown to play a role in regulating leukocyte homing, immune cell surface phenotype and mature immune cell function. While the contribution of the β 2 -adrenergic receptor in inflammation is well established clinically, in view of their potent anti-inflammatory properties (Barnes, 1999;Cobelens et al, 2002;Sekut et al, 1995), its role in modulating leukocyte recruitment has received remarkably little attention (de Coupade et al, 2004;Straub et al, 2000b). The few studies investigating the role of β 2 -adrenergic receptor agonists on leukocyte function in vivo are mostly limited to examination of their effects on cytokine production and cell adhesion.…”

“…Since β 2 -adrenergic mechanisms have been reported to be sexually dimorphic (Barker et al, 2005;de Coupade et al, 2004;Hinojosa-Laborde et al, 1999;Krieg et al, 1986;Mills et al, 1996;Tan et al, 1997;Wheeldon et al, 1994), the present study investigated the ability of β 2 -adrenergic receptors to modulate neutrophil recruitment, using wild-type (FVB) and β 2 -adrenergic receptor knockout mice (bred on a congenic FVB background). Of note, in a comparison of inflammation in the lungs of 9 mouse strains, after ovalbumin sensitization and aerosol challenge the FVB strain had fewer infiltrating leukocytes than 4 other strains, but similar to BALB/C, C57/BL and C3H/HeJ strains (Whitehead et al, 2003).…”

S100A8 Triggers Oxidation-sensitive Repulsion of Neutrophils

“…The assays were adapted from methods previously described by others (Wu et al, 2001;Hanson and Quinn, 2002;de Coupade et al, 2004). Blood was obtained according to a protocol approved by the Committee on Human Research of the University of California, San Francisco (UCSF), with informed consent.…”