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AMPK activation attenuates inflammatory pain through inhibiting NF-?B activation and IL-1? expression.

ABSTRACT: BACKGROUND:Chronic pain is a major clinical problem with limited treatment options. Previous studies have demonstrated that activation of adenosine monophosphate-activated protein kinase (AMPK) can attenuate neuropathic pain. Inflammation/immune response at the site of complete Freund's adjuvant (CFA) injection is known to be a critical trigger of the pathological changes that produce inflammatory pain. However, whether activation of AMPK produces an analgesic effect through inhibiting the proinflammatory cytokines, including interleukin-1? (IL-1?), in inflammatory pain remains unknown. METHODS:Inflammatory pain was induced in mice injected with CFA. The effects of AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside, an AMPK activator), Compound C (an AMPK inhibitor), and IL-1ra (an IL-1 receptor antagonist) were tested at day 4 after CFA injection. Inflammatory pain was assessed with von Frey filaments and hot plate. Immunoblotting, hematoxylin and eosin (H&E) staining, and immunofluorescence were used to assess inflammation-induced biochemical changes. RESULTS:The AMPK activator AICAR produced an analgesic effect and inhibited the level of proinflammatory cytokine IL-1? in the inflamed skin in mice. Moreover, activation of AMPK suppressed CFA-induced NF-?B p65 translocation from the cytosol to the nucleus in activated macrophages (CD68+ and CX3CR1+) of inflamed skin tissues. Subcutaneous injection of IL-1ra attenuated CFA-induced inflammatory pain. The AMPK inhibitor Compound C and AMPK? shRNA reversed the analgesic effect of AICAR and the effects of AICAR on IL-1? and NF-?B activation in inflamed skin tissues. CONCLUSIONS:Our study provides new information that AMPK activation produces the analgesic effect by inhibiting NF-?B activation and reducing the expression of IL-1? in inflammatory pain.

SUBMITTER: Xiang HC

PROVIDER: S-EPMC6373126 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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AMPK activation attenuates inflammatory pain through inhibiting NF-κB activation and IL-1β expression.

Xiang Hong-Chun HC Lin Li-Xue LX Hu Xue-Fei XF Zhu He H Li Hong-Ping HP Zhang Ru-Yue RY Hu Liang L Liu Wen-Tao WT Zhao Yi-Lin YL Shu Yang Y Pan Hui-Lin HL Li Man M

Journal of neuroinflammation 20190212 1

<h4>Background</h4>Chronic pain is a major clinical problem with limited treatment options. Previous studies have demonstrated that activation of adenosine monophosphate-activated protein kinase (AMPK) can attenuate neuropathic pain. Inflammation/immune response at the site of complete Freund's adjuvant (CFA) injection is known to be a critical trigger of the pathological changes that produce inflammatory pain. However, whether activation of AMPK produces an analgesic effect through inhibiting t ...[more]

PMID: 30755236

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Project description:BACKGROUND:AMP-activated Protein Kinase (AMPK) is a stress-activated kinase that protects against cardiomyocyte injury during ischemia and reperfusion. c-Jun N-terminal kinase (JNK), a mitogen activated protein kinase, is activated by ischemia and reperfusion. NF-?B is an important transcription factor involved in ischemia and reperfusion injury. METHODS AND RESULTS:The intrinsic activation of AMPK attenuates the inflammation which occurred during ischemia/reperfusion through the modulation of the JNK mediated NF-?B signaling pathway. Rat cardiac myoblast H9c2 cells were subjected to hypoxia and/or reoxygenation to investigate the signal transduction that occurred during myocardial ischemia/reperfusion. Mitochondrial function was measured by the Seahorse XF24 V7 PS system. Hypoxia treatment triggered AMPK activation in H9c2 cells in a time dependent manner. The inhibition of hypoxic AMPK activation through a pharmacological approach (Compound C) or siRNA knockdown of AMPK ? catalytic subunits caused dramatic augmentation in JNK activation, inflammatory NF-?B phosphorylation, and apoptosis during hypoxia and reoxygenation. Inhibition of AMPK activation significantly impaired mitochondrial function and increased the generation of reactive oxygen species (ROS) during hypoxia and reoxygenation. In contrast, pharmacological activation of AMPK by metformin significantly inhibited mitochondrial permeability transition pore (mPTP) opening and ROS generation. Moreover, AMPK activation significantly attenuated the JNK-NF-?B signaling cascade and inhibited mRNA and protein levels of pro-inflammatory cytokines, such as TNF-? and IL-6, during hyopoxia/reoxygenation in H9c2 cells. Intriguingly, both pharmacologic inhibition of JNK by JNK-IN-8 and siRNA knockdown of JNK signaling pathway attenuated NF-?B phosphorylation and apoptosis but did not affect AMPK activation in response to hypoxia and reoxygenation. CONCLUSIONS:AMPK activation modulates JNK-NF-?B signaling cascade during hypoxia and reoxygenation stress conditions. Cardiac AMPK activation plays a critical role in maintaining mitochondrial function and inhibiting the inflammatory response caused by ischemic insults.

Dataset Information

AMPK activation attenuates inflammatory pain through inhibiting NF-?B activation and IL-1? expression.

Publications

AMPK activation attenuates inflammatory pain through inhibiting NF-κB activation and IL-1β expression.

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