Targeting Mitogen-Activated Protein Kinases for Asthma

Duan, Wei; Wong, W.S. Fred

doi:10.2174/138945006777435353

Cited by 121 publications

(78 citation statements)

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“…48,49 In addition, mounting evidence has revealed that the ERK and p38 MAPK cascades could regulate proliferation, differentiation, cytokine production, chemotaxis and apoptosis of various inflammatory cells, including Th2 lymphocytes, mast cells and eosinophils. 49,50 Therefore, the activation of the NF-kB, ERK and p38 MAPK pathways in IL-1b-, IL-18-and IL-33-induced eosinophil activation further confirms the importance of these signal transduction pathways in the pathogenesis of allergic inflammation.…”

Section: Il-33 Activates Eosinophilsmentioning

confidence: 57%

Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation

et al. 2009

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The novel interleukin (IL)-1 family cytokine IL-33 has been shown to activate T helper 2 (Th2) lymphocytes, mast cells and basophils to produce an array of proinflammatory cytokines, as well as to mediate blood eosinophilia, IgE secretion and hypertrophy of airway epithelium in mice. In the present study, we characterized the activation of human eosinophils by IL-33, and investigated the underlying intracellular signaling mechanisms. IL-33 markedly enhanced eosinophil survival and upregulated cell surface expression of the adhesion molecule intercellular adhesion molecule (ICAM)-1 on eosinophils, but it suppressed that of ICAM-3 and L-selectin. In addition, IL-33 mediates significant release of the proinflammatory cytokine IL-6 and the chemokines CXCL8 and CCL2. We found that IL-33-mediated enhancement of survival, induction of adhesion molecules, and release of cytokines and chemokines were differentially regulated by activation of the nuclear factor (NF)-kB, p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) pathways. Furthermore, we compared the above IL-33 activities with two structurally and functionally related cytokines, IL-1b and IL-18. IL-1b, but not IL-18, markedly upregulated cell surface expression of ICAM-1. IL-1b and IL-18 also significantly enhanced eosinophil survival, and induced the release of IL-6 and chemokines CXCL8 and CCL2 via the activation of the NF-kB, p38 MAPK and ERK pathways. Synergistic effects on the release of IL-6 were also observed in combined treatment with IL-1b, IL-18 and IL-33. Taken together, our findings provide insight into IL-33-mediated activation of eosinophils via differential intracellular signaling cascades in the immunopathogenesis of allergic inflammation.

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Section: Il-33 Activates Eosinophilsmentioning

confidence: 57%

Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation

et al. 2009

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“…Moreover, this lack of phosphorylation of Erk on an activating residue is consistent with the lack of an enhancement of proliferation in response to PEMF that we observed in the UMR line (data not shown), and the same lack of proliferation reported in the MC3T3-E1 cell type (T. Patterson, personal communication). Erk is thought to play a role in the proliferation of most cell types 26 and PEMF's failure to induce an enhancement in Erk phosphorylation is consistent with this biological event.…”

Section: Discussionmentioning

confidence: 88%

Pulsed electromagnetic fields rapidly modulate intracellular signaling events in osteoblastic cells: Comparison to parathyroid hormone and insulin

Schnoke

Midura

2007

Journal Orthopaedic Research

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Pulsed electromagnetic field (PEMF) devices are approved for the healing of bone nonunions, but there is a lack of understanding as to their mechanism of action at the cell and molecular level. Intermittent parathyroid hormone (PTH) therapy is currently utilized for treatment of osteoporosis, and is also being investigated for the purpose of augmenting fracture healing. Insulin and IGF-1 are also thought to play important anabolic roles in osteogenesis. In this report, signaling pathways activated by acute PTH or insulin treatments were compared to those activated by PEMF treatment in osteoblast-like cells. Some signaling molecules like the extracellular response kinases 1/2 (Erk1/2) and the cAMP response element binding protein (CREB) were activated by insulin and PTH, respectively, but not by PEMF treatment. Other signaling molecules like the insulin receptor substrate-1 (IRS-1), the S6 ribosomal subunit kinase, and the endothelial nitric oxide synthase (eNOS) were phosphorylated by PTH, insulin, and PEMF to the same relative extent and within the same time frame. IRS-1, eNOS, and S6 have been implicated in bone anabolism, and our results suggest that the anabolic effects of PEMF may be mediated, in part, through the activation of these proteins. ß

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“…MAPKs are also well-recognized mediators of mast cell activation, survival, differentiation and cytokine production. Clinical development of small molecule inhibitors of the p38 MAPK are presently ongoing [151][152][153]. Phosphodiesterase 4 (PDE4) is the major cyclic-AMP metabolizing enzyme in immune and inflammatory cells, including mast cells.…”

Section: Intracellular Targetsmentioning

confidence: 99%

The mast cell and allergic diseases: role in pathogenesis and implications for therapy

Brown

Wilson

Metcalfe

2007

Clin Experimental Allergy

221

184

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SummaryMast cells have long been recognized for their role in the genesis of allergic inflammation; and more recently for their participation in innate and acquired immune responses. Mast cells reside within tissues including the skin and mucosal membranes, which interface with the external environment; as well as being found within vascularized tissues next to nerves, blood vessels and glandular structures. Mast cells have the capability of reacting both within minutes and over hours to specific stimuli, with local and systemic effects. Mast cells express the high affinity IgE receptor (FceRI) and upon aggregation of FceRI by allergen-specific IgE, mast cells release and generate biologically active preformed and newly synthesized mediators which are involved in many aspects of allergic inflammation. While mast cells have been well documented to be essential for acute allergic reactions, more recently the importance of mast cells in reacting through pattern recognition receptors in innate immune responses has become recognized. Moreover, as our molecular understanding of the mast cell has evolved, novel targets for modulation have been identified with promising therapeutic potential.

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Targeting Mitogen-Activated Protein Kinases for Asthma

Cited by 121 publications

References 0 publications

Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation

Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation

Pulsed electromagnetic fields rapidly modulate intracellular signaling events in osteoblastic cells: Comparison to parathyroid hormone and insulin

The mast cell and allergic diseases: role in pathogenesis and implications for therapy

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