Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord

Taves, Sarah; Berta, Temugin; Liu, Da-Lu; Gan, Sophie; Chen, Gang; Kim, Yong Ho; Ven, Thomas Van de; Laufer, Stefan; Ji, Ru-Rong

doi:10.1016/j.bbi.2015.10.006

Cited by 253 publications

(241 citation statements)

References 78 publications

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“…Three distinct MAPK pathways have been described in mammalian cells, including the ERK pathway, the JNK pathway, and the p38 MAPK pathway (25). The present study demonstrated that transfection of SW48 cells with the TGFBR1*6A plasmid resulted in the upregulation of p-p38 and p-ERK protein expression.…”

Section: Discussionsupporting

confidence: 52%

TGFBR1*6A is a potential modifier of migration and invasion in colorectal cancer cells

et al. 2018

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Abstract. Type 1 transforming growth factor β receptor (TGFBR1)*6A, a common hypomorphic variant of TGFBR1, may act as a susceptibility allele in colorectal cancer. However, the contribution of TGFBR1*6A to colorectal cancer development is largely unknown. To test the hypothesis that TGFBR1*6A promotes colorectal cancer invasion and metastasis via Smad-independent transforming growth factor-β (TGF-β) signaling, the effect of TGFBR1*6A on the invasion of colorectal cancer cells was assessed. pCMV5-TGFBR1*6A-HA plasmids were transfected into SW48 and DLD-1 cells by Lipofectamine-mediated DNA transfection. The effect of TGF-β1 on the proliferation of SW48 and DLD-1 cells transfected with TGFBR1*6A was determined by MTT assay. The effects of the TGF-β1 on the invasion of the transfected SW48 and DLD-1 cells were determined using Matrigel-coated plates. Transforming migrating chambers were used to determine the effects of TGF-β1 on the migration of the transfected SW48 and DLD-1 cells. Western blot analysis was used to determine the expression of phosphorylated (p-) extracellular-signal-regulated kinase (ERK), p-P38 and p-SMAD family member 2 in SW48 cells. Using transfected TGFBR1*6A SW48 and DLD-1 cell lines our group demonstrated that, in comparison with TGFBR1*9A, TGFBR1*6A is capable of switching TGF-β1 growth-inhibitory signals into growth-stimulatory signals which significantly increased the invasion of SW48 and DLD-1 cells. Functional assays indicated that TGFBR1*6A weakened Smad-signaling but increased ERK and p38 signaling, which are crucial mediators of cell migration and invasion. From this, it was possible to conclude that TGFBR1*6A enhanced SW48 cell migration and invasion through the mitogen-activated protein kinase pathway and that it may contribute to colorectal cancer progression in a TGF-β1/Smad signaling-independent manner. This suggests that TGFBR1*6A may possess oncogenic properties and that it may affect the migration and invasion of colorectal cancer cells.

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Section: Discussionsupporting

confidence: 52%

TGFBR1*6A is a potential modifier of migration and invasion in colorectal cancer cells

et al. 2018

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“…Thus, strong or weak expression of p-p38 predicts whether nerve cells are alive (27). As a result of the apoptosis process of neurons and colloid cells subsequent to SCI, p-p38 expression increases, indicating that the p-p38 signal transduction pathway is altered after SCI (28). SCI results in the activation of p-p38, which then increases NOS activity and promotes apoptosis (29).…”

Section: Discussionmentioning

confidence: 99%

Anti‑inflammatory effect of delphinidin on intramedullary spinal pressure in a spinal cord injury rat model

Wang

Zhu

et al. 2017

Exp Ther Med

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Abstract. Delphinidin, a flavonoid polyphenolic compound, is widely found in nature and is used as a food supplement due to its pharmacological activity. The aims of the present study were to examine the anti-inflammatory effect of delphinidin in alleviating spinal cord injury (SCI)-induced inflammation in a rat model and to determine the underlying mechanisms in SCI. The Basso, Beattie, Bresnahan (BBB) scores of rats were assessed to evaluate the effect of delphinidin on the recovery of motor function. ELISA kits were also used to analyze the activities of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and caspase-3. In addition, the protein expression levels of nuclear factor (NF)-κB, activator protein 1 (AP-1) and p38-MAPK protein expression were measured using western blot analysis. Treatment with delphinidin significantly increased the BBB scores, as well as inhibited the intramedullary spinal pressure in SCI rats. Delphinidin treatment also significantly suppressed the levels of inflammatory factors and NF-κB protein expression in SCI rats. Finally, treatment with delphinidin significantly inhibited NF-κB stimulation, COX-2 activity, PGE2 production, and AP-1 and p38-MAPK protein expression in SCI rats. These results suggest that the anti-inflammatory effect of delphinidin alleviated inflammation in the SCI rat model via alleviation of the intramedullary spinal pressure through the NF-κB and p38-MAPK signaling pathways.

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“…Microglia have also been shown to be involved with orofacial pain (Fan et al 2010;Ma et al 2015); activation of the P2X7 receptor in microglia of trigeminal nucleus facilitates extraterritorial facial pain via TNF-α secretion following transection of the mental nerve, the third branch of the trigeminal nerve (Murasaki et al 2013). Recent studies have found that the role of microglia in pain also depends on sex (Sorge et al 2015;Taves et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Microglial Signaling in Chronic Pain with a Special Focus on Caspase 6, p38 MAP Kinase, and Sex Dependence

et al. 2016

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Microglia are the resident immune cells in the spinal cord and brain. Mounting evidence suggests that activation of microglia plays an important role in the pathogenesis of chronic pain, including chronic orofacial pain. In particular, microglia contribute to the transition from acute pain to chronic pain, as inhibition of microglial signaling reduces pathologic pain after inflammation, nerve injury, and cancer but not baseline pain. As compared with inflammation, nerve injury induces much more robust morphologic activation of microglia, termed microgliosis, as shown by increased expression of microglial markers, such as CD11b and IBA1. However, microglial signaling inhibitors effectively reduce inflammatory pain and neuropathic pain, arguing against the importance of morphologic activation of microglia in chronic pain sensitization. Importantly, microglia enhance pain states via secretion of proinflammatory and pronociceptive mediators, such as tumor necrosis factor α, interleukins 1β and 18, and brain-derived growth factor. Mechanistically, these mediators have been shown to enhance excitatory synaptic transmission and suppress inhibitory synaptic transmission in the pain circuits. While early studies suggested a predominant role of microglia in the induction of chronic pain, further studies have supported a role of microglia in the maintenance of chronic pain. Intriguingly, recent studies show male-dominant microglial signaling in some neuropathic pain and inflammatory pain states, although both sexes show identical morphologic activation of microglia after nerve injury. In this critical review, we provide evidence to show that caspase 6—a secreted protease that is expressed in primary afferent axonal terminals surrounding microglia—is a robust activator of microglia and induces profound release of tumor necrosis factor α from microglia via activation of p38 MAP kinase. The authors also show that microglial caspase 6/p38 signaling is male dominant in some inflammatory and neuropathic pain conditions. Finally, the authors discuss the relevance of microglial signaling in chronic trigeminal and orofacial pain.

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Spinal inhibition of p38 MAP kinase reduces inflammatory and neuropathic pain in male but not female mice: Sex-dependent microglial signaling in the spinal cord

Cited by 253 publications

References 78 publications

TGFBR1*6A is a potential modifier of migration and invasion in colorectal cancer cells

TGFBR1*6A is a potential modifier of migration and invasion in colorectal cancer cells

Anti‑inflammatory effect of delphinidin on intramedullary spinal pressure in a spinal cord injury rat model

Microglial Signaling in Chronic Pain with a Special Focus on Caspase 6, p38 MAP Kinase, and Sex Dependence

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