α₁-Adrenergic Receptors Positively Regulate Toll-Like Receptor Cytokine Production from Human Monocytes and Macrophages

Abstract

Catecholamines released from the sympathetic nervous system in response to stress or injury affect expression of inflammatory cytokines generated by immune cells. ␣ 1 -Adrenergic receptors (ARs) are expressed on innate immune cell populations, but their subtype expression patterns and signaling characteristics are not well characterized. Primary human monocytes, a human monocytic cell line, and monocyte-derived macrophage cells were used to measure expression of the proinflammatory mediator interleukin (IL)-1␤ responding to lipopolysaccharide (LPS) in the presence or absence of ␣ 1 -AR activation. Based on our previous findings, we hypothesized that ␣ 1 -AR stimulation on innate immune cells positively regulates LPS-initiated IL-1␤ production. IL-1␤ production in response to LPS was synergistically higher for both monocytes and macrophages in the presence of the selective ␣ 1 -AR agonist (R)-(Ϫ)-phenylephrine hydrochloride (PE). This synergistic IL-1␤ response could be blocked with a selective ␣ 1 -AR antagonist as well as inhibitors of protein kinase C (PKC). Radioligand binding studies characterized a homogenous ␣ 1B -AR subtype population on monocytes, which changed to a heterogeneous receptor subtype expression pattern when differentiated to macrophages. Furthermore, increased p38 mitogenactivated protein kinase (MAPK) activation was observed only with concurrent PE and LPS stimulation, peaking after 120 and 30 min in monocytes and macrophages, respectively. Blocking the PKC/p38 MAPK signaling pathway in both innate immune cell types inhibited the synergistic IL-1␤ increase observed with concurrent PE and LPS treatments. This study characterizes ␣ 1 -AR subtype expression on both human monocyte and macrophage cells and illustrates a mechanism by which increased IL-1␤ production can be modulated by ␣ 1 -AR input.

Adrenergic stimulation alters the expression of inflammasome components and interleukins in primary human monocytes

“…1A). These findings are consistent with the results of Grisanti et al (22), which presented increased levels of supernatant IL-1β in primary human monocytes co-stimulated with LPS + PE compared with LPS-stimulation alone, results which may be associated with increased p38 MAPK activity. However, in contrast to the observed increase in pro-IL-1β concentration within the cytosol in Gristanti et al (22), the gene expression levels of IL-1β were reduced in the present study.…”

“…These findings are consistent with the results of Grisanti et al (22), which presented increased levels of supernatant IL-1β in primary human monocytes co-stimulated with LPS + PE compared with LPS-stimulation alone, results which may be associated with increased p38 MAPK activity. However, in contrast to the observed increase in pro-IL-1β concentration within the cytosol in Gristanti et al (22), the gene expression levels of IL-1β were reduced in the present study. These data indicate that the enhancing effects of PE co-stimulation on IL-1β secretion following LPS application may occur on a post-genomic level, possibly as a result of increased IL-1β mRNA stability, as has been described previously for p38 MAPK activation (33,34).…”

“…These data indicate that the enhancing effects of PE co-stimulation on IL-1β secretion following LPS application may occur on a post-genomic level, possibly as a result of increased IL-1β mRNA stability, as has been described previously for p38 MAPK activation (33,34). However, the present study and the prior study by Grisanti et al (22) indicate that PE-stimulation alone does not stimulate IL-1β expression in human primary monocytes. Regarding IL-18, the results of the present study were unexpected.…”

“…Previous studies have indicated that adrenergic stimulation induced p38 mitogen-activated protein kinase (MAPK) phosphorylation. Although IL-1β generation does not seem to require p38 MAPK activation, synergistic effects with the nuclear factor-κB (NF-κB) pathway appear to be mediated via this signal in a number of contexts (22,24). In addition to the gene expression of pro-IL-1β, NLRP3 gene expression is induced by NF-κB activation (25,26).…”

“…Previous studies that investigated the effect of catecholamines on human monocytes revealed an increase in the secretion of a number of proinflammatory cytokines, notably IL-1β (22,23). Grisanti et al (22) demonstrated that the application of phenylephrine (PE) increased the intracellular load of the 31-kD progenitor pro-IL-1β and enhanced IL-1β protein expression in human monocytes.…”