SDF-1alpha up-regulates interleukin-6 through CXCR4, PI3K/Akt, ERK, and NF-kappaB-dependent pathway in microglia

Lu, Dah‐Yuu; Tang, Chih‐Hsin; Yeh, Wei-Lan; Wong, Kar‐Lok; Lin, Chih-Peng; Chen, Yi‐Hung; Lai, Chih‐Ho; Chen, Yuh‐Fung; Leung, Yuk‐Man; Fu, Wen‐Mei

doi:10.1016/j.ejphar.2009.03.001

Cited by 107 publications

(80 citation statements)

References 38 publications

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“…ERK-and Akt-dependent activation of NF-B correlated with enhanced phosphorylation and degradation of IB-␣, an inhibitor of NF-B that keeps it sequestered in the cytoplasm. A similar mechanism of NF-B activation by Akt and ERK has been reported earlier by others, which likely involves phosphorylation of IB kinase (IKK), a kinase that phosphorylates the IB inhibitor protein (21,49). A role of NF-B has also been reported previously in SHH regulation through direct binding and transactivation of its promoter.…”

Section: Discussionmentioning

confidence: 71%

“…CXCL12 induces receptor phosphorylation, which leads to conformational changes and subsequent activation of a heterotrimeric G protein complex bound to the receptor intracellular domain, thus initiating downstream signaling (11). We and others have reported earlier that treatment of pancreatic cancer cells with CXCL12 elicits the activation of Akt and ERK (17,21,22). Activation of Akt and ERK by CXCL12 occurs as early as 1 min and starts diminishing by 30 min post-treatment (supplemental Fig.…”

Section: Cxcl12 Induces the Expression Of Shh In Pancreatic Cancermentioning

confidence: 99%

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CXCL12/CXCR4 Protein Signaling Axis Induces Sonic Hedgehog Expression in Pancreatic Cancer Cells via Extracellular Regulated Kinase- and Akt Kinase-mediated Activation of Nuclear Factor κB

Singh

Arora

Bhardwaj

et al. 2012

Journal of Biological Chemistry

106

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Background: CXCL12/CXCR4 and hedgehog pathways, predominantly acting in paracrine fashion, play important roles in pancreatic cancer pathobiology. Results: CXCL12/CXCR4 signaling regulates the expression of hedgehog ligand, the sonic hedgehog, in pancreatic cancer cells. Conclusion: Our findings indicate a novel molecular link between CXCL12/CXCR4 and hedgehog pathways. Significance: Our data provide a molecular basis for an active bidirectional tumor-stromal interaction in pancreatic cancer.

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Section: Discussionmentioning

confidence: 71%

Section: Cxcl12 Induces the Expression Of Shh In Pancreatic Cancermentioning

confidence: 99%

CXCL12/CXCR4 Protein Signaling Axis Induces Sonic Hedgehog Expression in Pancreatic Cancer Cells via Extracellular Regulated Kinase- and Akt Kinase-mediated Activation of Nuclear Factor κB

Singh

Arora

Bhardwaj

et al. 2012

Journal of Biological Chemistry

106

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“…In the central nervous system, HMGB1 seems to regulate microglial activation and the subsequent production of proinflammatory cytokines (15). Previous stud-ies demonstrated that CXCR4 signaling induces microglial activation, MAPK p42/44 phosphorylation, and the expression of interleukin-6 (IL-6) and tumor necrosis factor-␣ (TNF-␣) (5,30). These findings suggest a novel mechanism that could drive inflammation-induced autonomic dysfunction in hypertension.…”

Section: Spontaneously Hypertensive Rats Have Increased Hmgb1 Contentmentioning

confidence: 89%

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

Masson

Nair

Soares

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Masson GS, Nair AR, Silva Soares PP, Michelini LC, Francis J. Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR. Am J Physiol Heart Circ Physiol 309: H1115-H1122, 2015. First published August 7, 2015; doi:10.1152/ajpheart.00349.2015.-Exercise training (ExT) is recommended to treat hypertension along with pharmaceutical antihypertensive therapies. Effects of ExT in hypothalamic content of high mobility box 1 (HMGB1) and microglial activation remain unknown. We examined whether ExT would decrease autonomic and cardiovascular abnormalities in spontaneously hypertensive rats (SHR), and whether these effects were associated with decreased HMGB1 content, microglial activation, and inflammation in the hypothalamic paraventricular nucleus (PVN). Normotensive Wistar-Kyoto (WKY) rats and SHR underwent moderate-intensity ExT for 2 wk. After ExT, cardiovascular (heart rate and arterial pressure) and autonomic parameters (arterial pressure and heart rate variability, peripheral sympathetic activity, cardiac vagal activity, and baroreflex function) were measured in conscious and freely-moving rats through chronic arterial and venous catheterization. Cerebrospinal fluid, plasma, and brain were collected for molecular and immunohistochemistry analyses of the PVN. In addition to reduced heart rate variability, decreased vagal cardiac activity and increased mean arterial pressure, heart rate, arterial pressure variability, cardiac, and vasomotor sympathetic activity, SHR had higher HMGB1 protein expression, IB-␣ phosphorylation, TNF-␣ and IL-6 protein expression, and microglia activation in the PVN. These changes were accompanied by higher plasma and cerebrospinal fluid levels of HMGB1. The ExT ϩ SHR group had decreased expression of HMGB1, CXCR4, SDF-1, and phosphorylation of p42/44 and IB-␣. ExT reduced microglial activation and proinflammatory cytokines content in the PVN, and improved autonomic control as well. Data suggest that training-induced downregulation of activated HMGB1/CXCR4/microglia/proinflammatory cytokines axis in the PVN of SHR is a prompt neural adaptation to counterbalance the deleterious effects of inflammation on autonomic control. exercise training; baroreflex; brain inflammation; CXCR4; hypertension NEW & NOTEWORTHY Spontaneously hypertensive rats have increased HMGB1 content and CXCR4 signaling in the hypothalamic paraventricular nucleus, which contributes to microglial activation, proinflammatory cytokines production, and, finally, to autonomic dysfunction. Aerobic training decreases HMGB1 content, microglia activation and proinflammatory cytokines expression by inhibiting HMGB1-CXCR4 signaling pathway in the hypothalamic paraventricular nucleus. Aerobic training induces neuroinflammatory adaptations and autonomic benefits independent of the arterial pressure fall.AUTONOMIC DYSFUNCTION is defined as a misbalance between sympathetic and vagal activity associated with baroreflex dysfunction and increased a...

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“…31 CXCL12 increases the mRNA expression and secretion of IL-6 in cultured microglia. 32 Our real-time PCR and ELISA data show that blocking CXCL12 signaling with AMD3100 reduced IL-6 mRNA levels at 24 hours after MCAO and subsequently reduced IL-6 plasma levels at 48 hours postischemia, suggesting that CXCL12 is an upstream regulator of IL-6 gene expression.…”

Section: January 2013mentioning

confidence: 95%

CXCR4 Antagonist AMD3100 Protects Blood–Brain Barrier Integrity and Reduces Inflammatory Response After Focal Ischemia in Mice

Huang

Tang

et al. 2013

Stroke

178

179

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Background and Purpose-Inflammatory response plays a critical role in propagating tissue damage after focal cerebral ischemia. CXCL12 is a key chemokine for leukocyte recruitment. However, the role of CXCL12 and its receptor CXCR4 in ischemia-induced inflammatory response is unclear. Here we use the pharmacological antagonist of CXCR4, AMD3100, to investigate the function of CXCL12/CXCR4 in regulating inflammatory response during acute ischemia. Methods-Adult male CD-1 mice (n=184) underwent permanent suture middle cerebral artery occlusion (MCAO). AMD3100 was injected for 3 days (1 mg/kg/day) after MCAO. Brain water content, infarct volume, neurological score, and myeloperoxidase (MPO) expression and activity were examined at 24, 48, and 72 hours after MCAO. Proinflammatory cytokine RNA and protein levels in brain tissue were measured by RT-PCR and enzyme linked immunosorbent assay. Results-Neurological score was greatly improved in AMD3100-treated mice compared with the control mice 3 days after MCAO (P<0.05). Brain edema-induced change of water content, IgG protein leakage, Evans blue extravasation, occludin, and ZO-1 expression in ipsilateral hemisphere were alleviated by acute treatment of AMD3100. MPO expression and activity revealed that AMD3100 profoundly reduced the number of MPO-positive cells in the ischemic region (P<0.05). It also attenuated proinflammatory cytokines including interleukin 6, tumor necrosis factor α, and interferon γ; their mRNA and protein levels changed accordingly compared with the controls (P<0.05). Conclusions-CXCR4 antagonist AMD3100 significantly suppressed inflammatory response and reduced blood-brain barrier disruption after MCAO. AMD3100 attenuated ischemia-induced acute inflammation by suppressing leukocyte migration and infiltration, in addition to reducing proinflammatory cytokine expression in the ischemic region.

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SDF-1alpha up-regulates interleukin-6 through CXCR4, PI3K/Akt, ERK, and NF-kappaB-dependent pathway in microglia

Cited by 107 publications

References 38 publications

CXCL12/CXCR4 Protein Signaling Axis Induces Sonic Hedgehog Expression in Pancreatic Cancer Cells via Extracellular Regulated Kinase- and Akt Kinase-mediated Activation of Nuclear Factor κB

CXCL12/CXCR4 Protein Signaling Axis Induces Sonic Hedgehog Expression in Pancreatic Cancer Cells via Extracellular Regulated Kinase- and Akt Kinase-mediated Activation of Nuclear Factor κB

Aerobic training normalizes autonomic dysfunction, HMGB1 content, microglia activation and inflammation in hypothalamic paraventricular nucleus of SHR

CXCR4 Antagonist AMD3100 Protects Blood–Brain Barrier Integrity and Reduces Inflammatory Response After Focal Ischemia in Mice

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