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Stolk, RF;Bruse, N;Jansen, A;Ponce, IR;
Genetic variation is an important determinant of the host response in sepsis patients.
Moreover, a specific genetic variant in the β2-adrenergic receptor was associated
with increased mortality in sepsis. Recently, it was discovered that the vasopressor
noradrenaline, ubiquitously used in septic shock patients, exerts profound anti-inflammatory effects and may contribute to sepsis-induced immunoparalysis via
stimulation of the β2-adrenergic receptor. In the present study, we evaluated whether
common non-synonymous variants (individual single nucleotide polymorphisms [SNPs]
or SNP haplotypes) in the β2-adrenergic receptor render subjects more susceptible for
noradrenaline-induced immunosuppression and whether they are associated with a
dysregulated systemic inflammatory response in vivo.
Peripheral blood mononuclear cells (PBMCs) of 109 healthy volunteers (52 female, 57
male) were ex vivo stimulated with 10 ng/mL lipopolysaccharide (LPS) in the presence
and absence of 1 µM noradrenaline, after which production of cytokines TNF, IL-6
and IL-10 was assessed. The same cohort of volunteers subsequently underwent
experimental endotoxemia (intravenous administration of 1 ng/kg LPS), during which
plasma concentrations of TNF, IL-6, IL-8, IL-10, IP-10, G-CSF, MCP-1, IL1-RA, and MIP1α were measured. Furthermore, mean arterial pressure, heart rate, and temperature
were recorded. Subjects were genotyped and common SNPs in the ADRB2 gene were
extracted (rs1042711, rs1042713 and rs1042714). Furthermore, the presence of common
haplotypes of these SNPs was assessed (CysGlyGln, CysArgGln, and ArgGlyGlu). Linear
regression models were used to evaluate associations between polymorphisms and ex vivo
as well as in vivo cytokine production, and hemodynamic parameters and temperature.
Noradrenaline attenuated production of the pro-inflammatory cytokines TNF and IL-6
(-26% (-22% to -30%), and -14% (-9% to -18%), respectively, both p<0.0001), and enhanced release of the anti-inflammatory mediator IL-10 (+9% (+3% to +15%), p=0.003) by ex vivostimulated PBMCs, but this was not affected by the presence of ADRB2 SNPs or haplotypes (all p-values ->0.37). In addition, no influence of SNPs or haplotypes on in vivo cytokine
levels, hemodynamic parameters, and temperature were observed (all p-values ->0.14).
Common non-synonymous variants in the ADRB2 gene do not influence noradrenaline mediated immunosuppression ex vivo or the systemic inflammatory and hemodynamic
response induced by LPS administration in healthy volunteers.