Leukotriene D4 and prostaglandin E2 signals synergize and potentiate vascular inflammation in a mast cell-dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3.
Animals; c-fos; Capillary Permeability; Cell Line; CysLT(1)R; Dinoprostone/*immunology; E-prostanoid receptor 3; Edema/immunology; EP3 Subtype/*immunology; extracellular signal-regulated kinase; Humans; Inbred BALB C; Inbred C57BL; Inflammation/immunology; leukotriene D(4); Leukotriene D4/*immunology; Leukotriene/*immunology; macrophage inflammatory protein 1beta; Mast cells; Mast Cells/*immunology; Mice; prostaglandin D(2); Prostaglandin E; prostaglandin E(2); protein kinase G; Receptors; Transgenic; Tumor
BACKGROUND: Although arachidonic acid metabolites, cysteinyl leukotrienes (cys-LTs; leukotriene [LT] C4, LTD4, and LTE4), and prostaglandin (PG) E2 are generated at the site of inflammation, it is not known whether crosstalk exists between these 2 classes of inflammatory mediators. OBJECTIVE: We sought to determine the role of LTD4-PGE2 crosstalk in inducing vascular inflammation in vivo, identify effector cells, and ascertain specific receptors and pathways involved in vitro. METHODS: Vascular (ear) inflammation was assessed by injecting agonists into mouse ears, followed by measuring ear thickness and histology, calcium influx with Fura-2, phosphorylation and expression of signaling molecules by means of immunoblotting, PGD2 and macrophage inflammatory protein 1beta generation by using ELISA, and expression of transcripts by using RT-PCR. Candidate receptors and signaling molecules were identified by using antagonists and inhibitors and confirmed by using small interfering RNA. RESULTS: LTD4 plus PGE2 potentiated vascular permeability and edema, gearing the system toward proinflammation in wild-type mice but not in Kit(W-sh) mice. Furthermore, LTD4 plus PGE2, through cysteinyl leukotriene receptor 1 (CysLT1R) and E-prostanoid receptor (EP) 3, enhanced extracellular signal-regulated kinase (Erk) and c-fos phosphorylation, inflammatory gene expression, macrophage inflammatory protein 1beta secretion, COX-2 upregulation, and PGD2 generation in mast cells. Additionally, we uncovered that this synergism is mediated through Gi, protein kinase G, and Erk signaling. LTD4 plus PGE2-potentiated effects are partially sensitive to CysLT1R or EP3 antagonists but completely abolished by simultaneous treatment both in vitro and in vivo. CONCLUSIONS: Our results unravel a unique
Kondeti Vinay; Al-Azzam Nosayba; Duah Ernest; Thodeti Charles K; Boyce Joshua A; Paruchuri Sailaja
The Journal of allergy and clinical immunology
2016
2016-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.jaci.2015.06.030" target="_blank" rel="noreferrer noopener">10.1016/j.jaci.2015.06.030</a>
Osteopetrosis: Therapeutic strategies
autosomal recessive osteopetrosis; bone-marrow transplantation; c-fos; defect; Endocrinology & Metabolism; malignant osteopetrosis; mice; osteoclasts; rats; resorption
Osteopetrosis describes a heterogeneous group of congenital bone disorders characterized by a generalized increase in skeletal mass resulting from a primary reduction in osteoclast mediated bone resorption, The pathogenetic heterogeneity is due to differences in the mutated gene that adversely affect the development or activation of the osteo clast. There are numerous naturally occurring and induced osteopetrotic mutations in animals; like wise, children afflicted with this disease also fall inter various subgroups. The molecular basis for the disease has been determined in some animal mutations, but little is known concerning the etiology of osteopetrosis in most forms in humans. This review will focus on the genetic defects associated with osteopetrosis that have been identified to date and will demonstrate how experimental studies in animal models of osteopetrosis have led to the use of bone marrow transplantation and other alternative strategies to treat osteopetrosis in humans, The clinical outcomes of these therapeutic strategies and potential therapies for use in the future will be discussed. From this review it should be come evident that studies of osteopetrosis in animals will continue to identify the molecular causes for other forms of the disease and to provide information that will help develop new strategies for treatment. In addition, the information gained from these experimental studies is likely to shed additional light on osteoclast biology as well as on broader aspects of skeletal diseases such as inflammation-mediated bone loss and osteoporosis.
Schneider G B; Key L L; Popoff S N
Endocrinologist
1998
1998-11
Journal Article
<a href="http://doi.org/10.1097/00019616-199811000-00004" target="_blank" rel="noreferrer noopener">10.1097/00019616-199811000-00004</a>