Cell Death Dis
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TNF-related apoptosis-inducing ligand (TRAIL) is a promising cytokine for killing tumor cells. However, a number of studies have demonstrated that different cancer cells resist TRAIL treatment and, moreover, TRAIL can promote invasion and metastasis in resistant cells. Here we report that TRAIL rapidly activates caspase-8 in a panel of non-small-cell lung carcinomas (NSCLCs). ⋯ Furthermore, chelation of intracellular Ca(2+) or inhibition of calmodulin caused a rapid proteasomal degradation of c-FLIPS, a significant increase of the two-step processing of procaspase-8, and reduced clonogenicity in response to TRAIL. Thus, our results revealed that the upregulation of DR4 and caspase-8 expression in NSCLC cells make them more susceptible to TRAIL. However, these cells could survive TRAIL treatment via upregulation of c-FLIPS, and it is suggested that blocking c-FLIPS expression by inhibition of Ca(2+)/calmodulin signaling significantly overcomes the acquired resistance of NSCLC cells to TRAIL.
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Cytokines such as interleukins are known to be involved in the development of neuropathic pain through activation of neuroglia. However, the role of chemokine (C-C motif) ligand 1 (CCL-1), a well-characterized chemokine secreted by activated T cells, in the nociceptive transmission remains unclear. We found that CCL-1 was upregulated in the spinal dorsal horn after partial sciatic nerve ligation. ⋯ Injection of CCL-1 also upregulated mRNA level of glial cell markers and proinflammatory cytokines (IL-1β, TNF-α and IL-6). The tactile allodynia induced by nerve ligation was attenuated by prophylactic and chronic administration of neutralizing antibody against CCL-1 and by knocking down of CCR-8. Our results indicate that CCL-1 is one of the key molecules in pathogenesis, and CCL-1/CCR-8 signaling system can be a potential target for drug development in the treatment for neuropathic pain.
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Traumatic brain injury (TBI) results in severe motor function impairment, and subsequent recovery is often incomplete. Rehabilitative training is considered to promote restoration of the injured neural network, thus facilitating functional recovery. However, no studies have assessed the effect of such trainings in the context of neural rewiring. ⋯ After the injury, the contralateral CST, labeled by biotinylated dextran amine, formed sprouting fibers into the denervated side of the cervical spinal cord. The number of these fibers was significantly higher in the TBI+rotarod group, whereas it did not increase in the TBI+reaching group. These results indicate that bilateral movement training effectively promotes axonal rewiring and motor function recovery, whereas the effect of simple repetitive training is limited.
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Activation of tumor necrosis factor receptor-1 can trigger survival or apoptosis pathways. In many cellular models, including the neuronal cell model PC12, it has been demonstrated that inhibition of protein synthesis is sufficient to render cells sensitive to apoptosis induced by TNFα. The survival effect is linked to the translocation of the transcription factor nuclear factor-kappa B (NF-κB) to the nucleus and activation of survival-related genes such as FLICE-like inhibitory protein long form (FLIP-L) or IAPs. ⋯ From a functional point of view, we show that inhibition of the MAPK/ERK pathway and the NF-κB pathway are equally relevant to render PC12 cells sensitive to cell death induced by TNFα. Apoptosis induced by TNFα under these conditions is dependent on jun nuclear kinase1/2 JNK1/2-dependent Bim upregulation. Therefore, we report a previously undescribed and essential role for MAPK/ERK activation by FLIP-L in the decision between cell survival and apoptosis upon TNFα stimulation.
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Microglia are the resident immune cells in the central nervous system and key players against pathogens and injury. However, persistent microglial activation often exacerbates pathological damage and has been implicated in many neurological diseases. Despite their pivotal physiological and pathophysiological roles, how the survival and death of activated microglia is regulated remains poorly understood. ⋯ Microglia from mice lacking functional TRIF were fully protected against TLR3/4 activation and zVAD-fmk-induced necrosis, and genetic deletion of rip3 also prevented microglia necroptosis. Activation of c-jun N-terminal kinase and generation of specific reactive oxygen species were downstream signaling events required for microglial cell death execution. Taken together, this study reveals a robust RIP3-dependent necroptosis signaling pathway in TLR-activated microglia upon caspase blockade and suggests that TLR signaling and programmed cell death pathways are closely linked in microglia, which could contribute to neuropathology and neuroinflammation when dysregulated.