Enhanced Phosphorylation of MAPKs by NE Promotes TNF-α Production by Macrophage Through α Adrenergic Receptor

Abstract

The aim of this study was to investigate whether norepinephrine (NE) could regulate macrophage production of tumor necrosis factor alpha (TNF-α) by influencing the phosphorylation of mitogen-activated protein kinases (MAPKs). Primary macrophages from male BALB/c mice were applied to explore the mechanism by which NE influences the the secretion of TNF-α when macrophages were activated by lipopolysaccharides (LPS). We found that NE could increase crophage production of TNF-α when macrophages were activated by LPS, and this effect could be inhibited by α adrenergic antagonist phentolamine. Also, NE could increase the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases (ERK), and p38, through α receptor. Furthermore, JNK inhibitor SP600125, ERK inhibitor U0126, and p38 inhibitor SB203580 could all partially counteract NE's effect on the phosphorylation of MAPKs, as well as TNF-α production by macrophages. This study revealed that as macrophages were activated by LPS, NE promoted the secretion of inflammatory factors by increasing the phosphorylation of MAPKs through an α receptor-dependent pathway. Our results provide the evidence of a relationship between stress and diseases, as well as the mechanism by which stress induces or affects the inflammation-related diseases.

Targeting α- and β-Adrenergic Receptors Differentially Shifts Th1, Th2, and Inflammatory Cytokine Profiles in Immune Organs to Attenuate Adjuvant Arthritis

“…This is in contrast to reports that β 2 -AR agonists and α-AR antagonists inhibit macrophage TNF-α production, respectively [reviewed in Ref. (74–77)]. These findings suggest an impairment of signaling via both β 2 - and α-ARs that occurs during the effector phase of AA.…”

“…The reduced pro-to-anti-inflammatory cytokine ratios are consistent with the well-known effects of β 2 -AR stimulation or α-AR blockade to inhibit TNF-α and promote IL-10 production in macrophages and dendritic cells (74–79). Spleen cells displayed the greatest drug-induced changes in anti-inflammatory profiles, largely due to greater IL-10 production.…”

Inflammation: The Common Pathway of Stress-Related Diseases

“…Besides GCs, the SNS and its main neurotransmitter, norepinephrine (NE) and neuropeptide Y (NPY), could regulate the immune and inflammatory function. NE promoted the secretion of inflammatory factors by increasing the phosphorylation of mitogen-activated protein kinases (MAPKs) through an α receptor-dependent pathway and NPY could elicit transforming growth factor-β (TGF-β) and TNFα production in macrophage-like cell line RAW264.7 via Y1 receptor (Bellinger et al, 2008; Zhou et al, 2008; Huang et al, 2012). …”

“…Noisy communities as life stressor induces significant increase in urine epinephrine and NE leading to hypertension (Seidman and Standring, 2010). NE promoted the production of inflammatory factors by facilitating the phosphorylation of MAPKs through activation of NE α receptor (Huang et al, 2012). NPY could elicit TGF-β1 and TNFα production in macrophage-like cell line RAW264.7 via Y1 receptor (von Känel et al, 2008).…”

Beta-adrenoceptor Activation by Norepinephrine Enhances Lipopolysaccharide-induced Matrix Metalloproteinase-9 Expression Through the ERK/JNK-c-Fos Pathway in Human THP-1 Cells

“…Although many previous reports have investigated the interaction between NE and LPS, they mainly focused on the effect of the cytokines release by NE and LPS 17, 18) . Speidl et al have demonstrated that catecholamines could potentiate LPS-induced expression of MMP-9 expression in U937 cells 19) ; however, little is known about the mechanism and pathway involved in this process.…”