Limits...
Upregulation of phagocyte-derived catecholamines augments the acute inflammatory response.

Flierl MA, Rittirsch D, Nadeau BA, Sarma JV, Day DE, Lentsch AB, Huber-Lang MS, Ward PA - PLoS ONE (2009)

Bottom Line: In adrenalectomized rats, development of ALI was enhanced and related to alpha(2)-adrenoceptors engagement but not to involvement of mineralocorticoid or glucocorticoid receptors.Collectively, these data demonstrate that catecholamines are potent inflammatory activators of macrophages, upregulating NFkappaB 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 alpha(2)-adrenoceptors.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.

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 NFkappaB in macrophages, causing enhanced release of proinflammatory cytokines (TNFalpha, IL-1beta, 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-beta-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 alpha(2)-adrenoceptors engagement but not to involvement of mineralocorticoid or glucocorticoid receptors. Collectively, these data demonstrate that catecholamines are potent inflammatory activators of macrophages, upregulating NFkappaB 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 alpha(2)-adrenoceptors.

Show MeSH

Related in: MedlinePlus

Following isolation, peritoneal mouse macrophages incubated to HBSS (negative conrol), LPS (20 ng/ml, positive control) or 10−11–10−8 M epinephrine (30 min, 37°C).Obtained supernatants were analyzed for TNF-α (A), IL-1β (B), IL-6 (C) and MIP-2 (D) using ELISA measurements. n = 4–7 per experimental group.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2636885&req=5

pone-0004414-g003: Following isolation, peritoneal mouse macrophages incubated to HBSS (negative conrol), LPS (20 ng/ml, positive control) or 10−11–10−8 M epinephrine (30 min, 37°C).Obtained supernatants were analyzed for TNF-α (A), IL-1β (B), IL-6 (C) and MIP-2 (D) using ELISA measurements. n = 4–7 per experimental group.

Mentions: This suggests induction of intracellular proinflammatory pathways by norepinephrine and epinephrine. To evaluate if this catecholamine-induced activation of NFκB was followed by increased downstream production of proinflammatory cytokines, peritoneal mouse macrophages were incubated for 4 hrs at 37°C with either HBSS (negative control), LPS (positive control, 20 ng/ml), or various doses of norepinephrine or epinephrine that lead to NFκB activation (10−11–10−8 M). The cell supernatant fluids were evaluated for TNFα, IL-1β and IL-6 and MIP-2 by ELISA. Exposure to norepinephrine or epinephrine not only induced activation of NFκB (Figure 1), but caused release of TNFα, IL-1β and IL-6 and MIP-2 from isolated macrophages in a dose dependent manner (Figures 2 and 3). Interestingly, 10−10 M norepinephrine or epinephrine alone caused ≥50% of the amounts of released cytokines when compared to macrophages incubated with LPS (20 ng/ml).


Upregulation of phagocyte-derived catecholamines augments the acute inflammatory response.

Flierl MA, Rittirsch D, Nadeau BA, Sarma JV, Day DE, Lentsch AB, Huber-Lang MS, Ward PA - PLoS ONE (2009)

Following isolation, peritoneal mouse macrophages incubated to HBSS (negative conrol), LPS (20 ng/ml, positive control) or 10−11–10−8 M epinephrine (30 min, 37°C).Obtained supernatants were analyzed for TNF-α (A), IL-1β (B), IL-6 (C) and MIP-2 (D) using ELISA measurements. n = 4–7 per experimental group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2636885&req=5

pone-0004414-g003: Following isolation, peritoneal mouse macrophages incubated to HBSS (negative conrol), LPS (20 ng/ml, positive control) or 10−11–10−8 M epinephrine (30 min, 37°C).Obtained supernatants were analyzed for TNF-α (A), IL-1β (B), IL-6 (C) and MIP-2 (D) using ELISA measurements. n = 4–7 per experimental group.
Mentions: This suggests induction of intracellular proinflammatory pathways by norepinephrine and epinephrine. To evaluate if this catecholamine-induced activation of NFκB was followed by increased downstream production of proinflammatory cytokines, peritoneal mouse macrophages were incubated for 4 hrs at 37°C with either HBSS (negative control), LPS (positive control, 20 ng/ml), or various doses of norepinephrine or epinephrine that lead to NFκB activation (10−11–10−8 M). The cell supernatant fluids were evaluated for TNFα, IL-1β and IL-6 and MIP-2 by ELISA. Exposure to norepinephrine or epinephrine not only induced activation of NFκB (Figure 1), but caused release of TNFα, IL-1β and IL-6 and MIP-2 from isolated macrophages in a dose dependent manner (Figures 2 and 3). Interestingly, 10−10 M norepinephrine or epinephrine alone caused ≥50% of the amounts of released cytokines when compared to macrophages incubated with LPS (20 ng/ml).

Bottom Line: In adrenalectomized rats, development of ALI was enhanced and related to alpha(2)-adrenoceptors engagement but not to involvement of mineralocorticoid or glucocorticoid receptors.Collectively, these data demonstrate that catecholamines are potent inflammatory activators of macrophages, upregulating NFkappaB 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 alpha(2)-adrenoceptors.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.

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 NFkappaB in macrophages, causing enhanced release of proinflammatory cytokines (TNFalpha, IL-1beta, 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-beta-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 alpha(2)-adrenoceptors engagement but not to involvement of mineralocorticoid or glucocorticoid receptors. Collectively, these data demonstrate that catecholamines are potent inflammatory activators of macrophages, upregulating NFkappaB 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 alpha(2)-adrenoceptors.

Show MeSH
Related in: MedlinePlus