Selective activation of STAT3 in human monocytes stimulated by G-CSF: implication in inhibition of LPS-induced TNF-α production

Nishiki, Saori; Hato, Fumihiko; Kamata, Noriko; Sakamoto, Erina; Hasegawa, Taro; Kimura-Eto, Akiko; Hino, Masayuki; Kitagawa, Seiichi

doi:10.1152/ajpcell.00387.2003

Cited by 65 publications

(50 citation statements)

References 60 publications

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“…54 While the mechanism governing G-CSF-mediated cytokine inhibition remains unclear, recent studies have suggested a role for STAT3. 58,59 Collectively, these data suggest an important role for G-CSF in the down-regulation of the local inflammatory response.…”

Section: Discussionmentioning

confidence: 83%

Regulation of systemic and local neutrophil responses by G-CSF during pulmonary Pseudomonas aeruginosa infection

Gregory¹,

Hogue

Ferkol

et al. 2006

Blood

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Granulocyte colony-stimulating factor (G-CSF) regulates the production, maturation, and function of neutrophils. Its expression is often induced during infection, resulting in high concentrations of G-CSF in inflammatory exudates and in the blood, suggesting that it may regulate both local and systemic neutrophil responses. Herein, we characterize the neutrophil response in G-CSFR−/− mice following intratracheal injection with Pseudomonas aeruginosa–laden agarose beads, modeling the pulmonary infection observed in many patients with cystic fibrosis. G-CSFR−/− mice are markedly susceptible to bronchopulmonary P aeruginosa infection, exhibiting decreased survival and bacterial clearance as well as extensive damage to lung tissue. The systemic neutrophil response was mediated primarily by enhanced neutrophil release from the bone marrow rather than increased neutrophil production and was attenuated in G-CSFR−/− mice. Despite normal to increased local production of inflammatory chemokines, neutrophil accumulation into the infected lung of G-CSFR−/− mice was markedly reduced. Moreover, the percentage of apoptotic neutrophils in the lung was elevated, suggesting that G-CSF signals may play an important role in regulating neutrophil survival at the inflammatory site. Collectively, these data provide new evidence that G-CSF signals play important but specific roles in the regulation of the systemic and local neutrophil response following infection.

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Section: Discussionmentioning

confidence: 83%

Regulation of systemic and local neutrophil responses by G-CSF during pulmonary Pseudomonas aeruginosa infection

Gregory¹,

Hogue

Ferkol

et al. 2006

Blood

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“…Accumulated evidence suggests that mitochondria play a critical role in macrophage-mediated innate immunity, and mitochondrial ROS generation is implicated in cytokine production and bactericidal activity in macrophages [43,44,45,46]. Our previous study shows that mitochondrial density and/or the respiratory state affect the level of mitochondrial ROS generation, which is closely associated with MAPK activation and cytokine production in macrophages stimulated with LPS [13,47]. …”

Section: Discussionmentioning

confidence: 97%

Stress-Induced Glucocorticoid Release Upregulates Uncoupling Protein-2 Expression and Enhances Resistance to Endotoxin-Induced Lethality

Kasahara

Sekiyama²,

Hori³

et al. 2015

Neuroimmunomodulation

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Objective: Although psychological and/or physiological stress has been well documented to influence immune responses, the precise mechanism for immunomodulation remains to be elucidated. The present work describes the role of the hypothalamic-pituitary-adrenal (HPA) axis in the mechanism of stress-mediated enhanced-resistance to lethality after lipopolysaccharide (LPS) injection. Methods/Results: Preconditioning with restraint stress (RS) resulted in enhanced activation of the HPA axis in response to LPS injection and suppressed LPS-induced release of proinflammatory cytokines and nitric oxide metabolites. Melanocortin 2 receptor-deficient mice (MC2R^-/-) failed to increase plasma levels of glucocorticoids in response to LPS injection, and exhibited high sensitivity to LPS-induced lethality with enhanced release of proinflammatory cytokines as compared with MC2R^+/- mice. Real-time PCR analysis revealed that RS induced upregulation of uncoupling protein-2 (UCP2) in macrophages in the lung and the liver of MC2R^+/-, but not of MC2R^-/-, mice. In addition, RS increased UCP2-dependent uncoupling activity of isolated mitochondria from the liver of MC2R^+/-, but not of MC2R^-/-, mice. In vitro study revealed that corticosterone and dexamethasone directly increased UCP2 expression in mouse RAW 264.7 macrophages and suppressed the generation of LPS-induced mitochondrial reactive oxygen species (ROS) and TNF-α production. Knockdown of UCP2 by small interfering RNA blunted the dexamethasone action for suppressing LPS-induced mitochondrial ROS and TNF-α production. Conclusion: The present work suggests that RS enhances activation of the HPA axis to release glucocorticoids and upregulation of UCP2 in macrophages, thereby increasing the resistance to endotoxin-induced systemic inflammation and death.

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“…These cascades include JAK2 -STAT3, PI3 Kinase -AKT, and ERK 1/2 (Nishiki et al, 2004, Schabitz et al, 2003, Schneider et al, 2005, Solaroglu et al, 2003. Recent work suggests that these intracellular cascades are upregulated selectively in different brain regions, and in different cell types within the brain.…”

Section: Introductionmentioning

confidence: 99%

The effect of granulocyte-colony stimulating factor in global cerebral ischemia in rats

Matchett¹,

Calinisan²,

Matchett³

et al. 2007

Brain Research

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Granulocyte-colony stimulating factor (G-CSF) is an endogenous peptide hormone of the hematopoietic system that has entered Phase I/II clinical trials for treatment of ischemic stroke. Severe intraoperative hypotension can lead to global cerebral ischemia and apoptotic neuron loss within the hippocampus. We tested G-CSF in a rat model of global cerebral ischemia. Global cerebral ischemia was induced in male Sprague-Dawley rats (280-330g) with the 2-vessel occlusion model (hemorrhagic hypotension to a mean arterial pressure of 30-35 mmHg and bilateral common carotid artery occlusion for 8 minutes). Three groups of animals were used: global ischemia without treatment (GI, n=49), global ischemia with G-CSF treatment (GI+G-CSF, n=42), and sham surgery (Sham, n = 26). Rats in the treatment group received G-CSF (50 μg / kg, subcutaneously) 12 hours before surgery, on the day of surgery, and on post-operative Day 1, and were euthanized on Day 2, 3, and 14. Mild hyperglycemia was observed in all groups. T-maze testing for spontaneous alternation demonstrated initial improvement in the G-CSF treatment group but no long-term benefit. Measurement of daily body weight demonstrated an initial trend toward improvement in the G-CSF group. Quantitative Nissl histology of the hippocampus demonstrated equivalent outcomes on Day 3 and 14, which was supported by quantitative TUNEL stain. Immunohistochemistry and Western blot demonstrated an initial increase in phosphorylated-AKT in the GI+G-CSF group on Day 2. We conclude that G-CSF treatment is associated with transient early improvement in neurobehavioral outcomes after global ischemia complicated by mild hyperglycemia, but no long-term protection.

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Selective activation of STAT3 in human monocytes stimulated by G-CSF: implication in inhibition of LPS-induced TNF-α production

Cited by 65 publications

References 60 publications

Regulation of systemic and local neutrophil responses by G-CSF during pulmonary Pseudomonas aeruginosa infection

Regulation of systemic and local neutrophil responses by G-CSF during pulmonary Pseudomonas aeruginosa infection

Stress-Induced Glucocorticoid Release Upregulates Uncoupling Protein-2 Expression and Enhances Resistance to Endotoxin-Induced Lethality

The effect of granulocyte-colony stimulating factor in global cerebral ischemia in rats

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