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The Role of MAP Kinases, Phosphatidylinositol 3-Kinase, and Ceramide in LPS-induced Signaling in Macrophages
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Anthony L. DeFranco, Alexander J. Finn, Julie Hambleton, Mary T. Crowley, Mary Lee MacKichan, Steven L. Weinstein
A form of the upstream component Raf that can be rapidly turned on was used to activate the Erkl/2 MAP kinases independently of LPS stimulation. Dr. Martin McMahon (UCSF Cancer Center, San Francisco, CA) developed a regulated form of Raf-1 by fusing the kinase domain of Raf-1 to the ligand-binding domain of the estrogen receptor. This chimeric protein (ARaf-1/ER) was rapidly activated in cells by addition of estradiol. Strong activation of Erkl/2 MAP kinases occurred within 15 minutes of the addition of estradiol (38). In collaborative experiments with Dr. McMahon we expressed the ARaf-l/ER fusion protein stably in RAW264.7 cells and tested the acute effects of its activation. As in fibroblasts, addition of estradiol to ARaf-1/ER-expressing RAW264.7 cells led to rapid and full activation of the Erkl and Erk2 MAP kinases. Interestingly, activation of these MAP kinases by Raf was stronger at later times (e.g., 4–48 hr) than was the activation seen in response to LPS (39). LPS-induced signals upstream of Erkl/2 may decrease with prolonged stimulation or, alternatively, LPS may induce a down-regulatory mechanism. In support of the latter possibility, we found that LPS induces the synthesis of the mkp-1 gene (39), which encodes a MAP kinase phosphatase (40), whereas activation of Raf and Erkl/2 MAP kinases by the ARaf-l/ER chimera does not. The presence of the mkp-1 gene product could decrease Erkl/2 phosphorylation, resulting in reduced enzymatic activity at later times following LPS stimulation.
Omega‐3 Polyunsaturated Fatty Acids and Lung Cancer: nutrition or Pharmacology?
Published in Nutrition and Cancer, 2021
Owen M. Vega, Shaheen Abkenari, Zhen Tong, Austin Tedman, Sara Huerta-Yepez
In addition, modulations in the expression of MAP-kinase-phosphatase-1(MKP-1) have been shown to be correlated with apoptosis of a variety of cancers, including breast, prostate, colon, bladder, and lung (59–62). In fact, a balance of MPK-1 and phosphatases is known to be correlated with the apoptosis (63). One study by Serini et al. aimed to analyze whether DHA PUFAs, which are known to inhibit proliferation and induce apoptosis in cancer cells, would also modulate the expression of MKP-1 in lung cancer cells (39, 64, 65). The research focused on A549 and BEN human lung squamous carcinoma cells. Cells were cultured in the presence of DHA, oleic acid (OA), LA, and AA. Results of the experiment demonstrated that apoptosis was not induced when lung cancer cells were treated with OA or the ω-6 PUFA LA. However, when treated with DHA and AA, lung cancer cells displayed an apoptotic effect. DHA was shown to induce MKP-1 expression, but AA, on the other hand, was unable to induce such effect. Results of the studies supported previous study allegations that therapeutic treatment of PUFA may serve to inhibit lung cancer proliferation (65).
Pathobionts: mechanisms of survival, expansion, and interaction with host with a focus on Clostridioides difficile
Published in Gut Microbes, 2021
Harish Chandra, Krishna Kant Sharma, Olli H. Tuovinen, Xingmin Sun, Pratyoosh Shukla
Li et al.77 reported the role of a MAP kinase phosphatase DUSP1 on inhibition of the MAPK activity. A knockout mutant of TRIM46, which ubiquitinates DUSP1, could inhibit TcdB-induced MAPK and NF-κB signaling, leading to the repression of TNF-α and IL-1β. Furthermore, the mutant inhibited the increased colonic inflammation induced by CDI.77 Additionally, the overexpression of the E3-ubiquitin ligase TRIM46 induced elevated levels of proinflammatory cytokines TNF-α and IL-1β. Li et al.77 also showed that these effects were mediated by binding of the TRIM46 to the promoter region of the NF-κBp65 subunit. In addition to pro-inflammatory mediators in acute colitis of CDI, inflammation was further accompanied by infiltration of immune cells.
Myeloid-Derived Suppressor Cells at the Intersection of Inflammaging and Bone Fragility
Published in Immunological Investigations, 2018
Keith L. Kirkwood, Lixia Zhang, Ramkumar Thiyagarajan, Kenneth L. Seldeen, Bruce R. Troen
The maintenance of bone homeostasis is dependent on the balance of activity of bone-resorbing osteoclasts and bone-forming osteoblasts (Boyle et al., 2003; Karsenty and Wagner, 2002; Duque et al., 2017). Abnormal bone resorption by osteoclasts results in bone destruction and is characteristic of bone-related diseases such as osteoporosis, rheumatoid arthritis, and periodontal disease (Feng and McDonald, 2011; Kirkwood et al., 2007). Osteoclasts are derived from monocyte/macrophage lineage cells. Formation of functional osteoclasts is dependent on macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) (Liu and Zhang, 2015; Troen, 2003; Duque et al., 2017). M-CSF permits abundance and survival of the osteoclasts precursor cells by acting through its receptor c-Fms to activate chiefly Akt and ERK1/2 (Gingery et al., 2003). RANKL promotes osteoclast differentiation, referred to as osteoclastogenesis, via its receptor RANK leading to recruitment of TNF receptor-associated factor 6 (TRAF6) and, in turn, activation of multiple downstream targets including mitogen-activated protein (MAP) kinases (MAPKs), activator protein-1, and NF-κB (Boyce, 2013). However, negative regulators of MAPK activation, primarily MAP kinase phosphatase-1, appear to be required for RANKL (physiological bone turnover) but inhibit pathological bone loss (Valerio et al., 2015, 2014; Valerio and Kirkwood, 2018). In addition, RANKL-driven osteoclastogenesis is dependent on the generation of a calcium signal through the activation of the immunoreceptor tyrosine-based activation motifs (ITAMs) of DNAX-activation protein 12 and Fc-receptor common γ subunit (FcRγ) (Boyce, 2013). This enables TRAF6-mediated and ITAM-mediated signals to interact cooperatively in transcriptional upregulation of nuclear factor of activated T-cells c1 (NFATc1, the master transcription factor).