U0126, an Inhibitor of MEK1/2, Increases Tumor Necrosis Factor-?-Induced Apoptosis, but not Interleukin-6 Induced Apoptosis in C-28/I2 Human Chondrocytes

Finegoldia magna, an Anaerobic Gram-Positive Bacterium of the Normal Human Microbiota, Induces Inflammation by Activating Neutrophils

“…Furthermore, manipulating the release of intracellular calcium ions (Ca 2+ ) using 2-ABP, demonstrated that the release of NETs, triggered by all stimuli, was significantly reduced, except for strain 505 ( Figure 3C). The ERK 1/2 pathway was previously described to be involved in NET formation (Munoz-Caro et al, 2015), and a common inhibitor of this pathway is U0126 (Malemud et al, 2015). In presence of this inhibitor, NET formation was reduced to control levels in the case of F. magna strain 312 and protein L, and significantly reduced when stimulated with strain ALB8 and protein FAF ( Figure 3D).…”

Pharmacologic Interventions for Preventing Chondrocyte Apoptosis in Rheumatoid Arthritis and Osteoarthritis

“…Analyses of synovial fluids and sera from RA and OA patients with active disease showed that these samples contained significantly elevated levels of various pro-inflammatory cytokines and growth factors when compared to a control group [52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68]. Of note, incubation of rat [69], non-arthritic or human chondrocytes from OA cartilage [70][71][72][73][74][75][76] or immortalized lines of human chondrocytes [77] with physiological levels of these cytokines, growth factors (e.g., VEGF and FGF) or additional soluble mediators (e.g., nitric oxide) were shown to induce apoptosis, which was accompanied by activation of SAPK/MAPK, JAK/STAT or PI3K/Akt/mTor signaling in these cells [78][79][80][81]. In addition, mediators of inflammation, including prostaglandin E 2 and neuropeptides (e.g., Substance P), are also implicated in perpetuating chronic inflammation [38].…”

“…These included, targeting x-linked inhibitor of apoptosis (XIAP), tumor necrosis factor-like weak inducer of apoptosis (TWEAK), TRAIL, decoy-receptor-3 (DcR3), tumor necrosis factor receptor protein-like molecules, p53 up-regulated modulator of apoptosis (PUMA), and apoptosis-signal-regulating kinases. In that regard, we proposed several interventional strategies which we acknowledged involved developing a deeper understanding of which signal transduction pathways were altered in RA and OA chondrocytes [19,28,36,77,82,106]. For example, XIAP, an inhibitor of activated caspase-9, and caspases-3 and -7 [82] was also shown to interact with mitogenactivated protein kinase kinase 2 (MEKK2) [139].…”

“…This finding is relevant to the regulation of chondrocyte apoptosis in both RA and OA primarily because XIAP is a well-known inhibitor of apoptosis protein-3 (IAP3) [140]. In fact, we had previously shown that recombinant human TNF-α (rhTNF-α) induced human chondrocyte apoptosis via activation of p38, JNK1/2 and STAT3 [72], whereas apoptosis of the immortalized human chondrocyte line, C-28/I2 induced by rhTNF-α, but not by rhIL-6, was dependent on upstream MEK1/2 [77]. Therefore, we posit that in order to consider using potential drug interventions that alter the activation of various signaling pathways it will be useful to consider what we know about how alterations in receptor-mediated signaling pathways (reviewed in [19]) may influence apoptosis.…”

“…The results of experimental studies cited in Refs. [70,72,77,80] were supported in part by grants from the National Institutes of Health, Takeda Pharmaceuticals of North America and Genentech/Roche Group.…”