Upregulation of Phagocyte-Derived Catecholamines Augments the Acute Inflammatory Response

Abstract

Following our recent report that phagocytic cells (neutrophils, PMNs, and macrophages) are newly discovered sources of catecholamines, we now show that both epinephrine and norepinephrine directly activate NFκB in macrophages, causing enhanced release of proinflammatory cytokines (TNFα, IL-1β, IL-6). Both adrenal-intact (AD+) and adrenalectomized (ADX) rodents were used, because ADX animals had greatly enhanced catecholamine release from phagocytes, facilitating our efforts to understand the role of catecholamines released from phagocytes. Phagocytes isolated from adrenalectomized rats displayed enhanced expression of tyrosine-hydroxylase and dopamine-β-hydroxylase, two key enzymes for catecholamine production and exhibited higher baseline secretion of norepinephrine and epinephrine. The effects of upregulation of phagocyte-derived catecholamines were investigated in two models of acute lung injury (ALI). Increased levels of phagocyte-derived catecholamines were associated with intensification of the acute inflammatory response, as assessed by increased plasma leak of albumin, enhanced myeloperoxidase content in lungs, augmented levels of proinflammatory mediators in bronchoalveolar lavage fluids, and elevated expression of pulmonary ICAM-1 and VCAM-1. In adrenalectomized rats, development of ALI was enhanced and related to α2-adrenoceptors engagement but not to involvement of mineralocorticoid or glucocorticoid receptors. Collectively, these data demonstrate that catecholamines are potent inflammatory activators of macrophages, upregulating NFκB and further downstream cytokine production of these cells. In adrenalectomized animals, which have been used to further assess the role of catecholamines, there appears to be a compensatory increase in catecholamine generating enzymes and catecholamines in macrophages, resulting in amplification of the acute inflammatory response via engagement of α2-adrenoceptors.

Norepinephrine Promotes the β1-Integrin–Mediated Adhesion of MDA-MB-231 Cells to Vascular Endothelium by the Induction of a GROα Release

“…NF-kB mediates the PPAR-induced upregulation of IL-8 in HUVECs (47). Several previous studies have shown for distinct cell types that norepinephrine is an activator of NF-kB (48) and thereby regulates the expression of proinflammatory chemokines and cytokines (49,50). In accordance with these findings, the addition of a NF-kB activation inhibitor reduced the norepinephrine induced adhesion of MDA-MB231 to endothelium in our flow-through adhesion assay.…”

Cardiovascular Problems on Hemodialysis

“…It has been shown that phagocytic cells produce catecholamines (48), which amplify inflammatory reactions (49). Microinflammation is a hallmark of the cardiovascular complications of uremia (50).…”

Acute cold exposure-induced down-regulation of CIDEA, cell death-inducing DNA fragmentation factor-α-like effector A, in rat interscapular brown adipose tissue by sympathetically activated β3-adrenoreceptors

“…Actually, TNF- treatment with human adipocytes decreased CIDEA gene expression [2]. In addition, norepinephrine induces the release of TNF- in mouse macrophages [29]. These findings suggest a possibility that TNF- released by activation of the sympathetic nervous system induces down-regulation of CIDEA expression in response to acute cold exposure in rat BAT.…”