Skip to main content
PMC home page
Mediators of Inflammation logoLink to Mediators of Inflammation
. 2003 Apr;12(2):79–87. doi: 10.1080/0962935031000097682

Signal transduction pathways in mast cell granule-mediated endothelial cell activation.

Luqi Chi 1, Lisa Stehno-Bittel 1, Irina Smirnova 1, Daniel J Stechschulte 1, Kottarappat N Dileepan 1
PMCID: PMC1781599  PMID: 12775357

Abstract

BACKGROUND: We have previously shown that incubation of human endothelial cells with mast cell granules results in potentiation of lipopolysaccharide-induced production of interleukin-6 and interleukin-8. AIMS: The objective of the present study was to identify candidate molecules and signal transduction pathways involved in the synergy between mast cell granules and lipopolysaccharide on endothelial cell activation. METHODS: Human umbilical vein endothelial cells were incubated with rat mast cell granules in the presence and absence of lipopolysaccharide, and IL-6 production was quantified. The status of c-Jun amino-terminal kinase and extracellular signal-regulated kinase 1/2 activation, nuclear factor-kappaB translocation and intracellular calcium levels were determined to identify the mechanism of synergy between mast cell granules and lipopolysaccaride. RESULTS: Mast cell granules induced low levels of interleukin-6 production by endothelial cells, and this effect was markedly enhanced by lipopolysaccharide. The results revealed that both serine proteases and histamine present in mast cell granules were involved in this activation process. Mast cell granules increased intracellular calcium, and activated c-Jun amino-terminal kinase and extracellular signal-regulated kinase 1/2. The combination of lipopolysaccharide and mast cell granules prolonged c-Jun amino-terminal kinase activity beyond the duration of induction by either stimulant alone and was entirely due to active proteases. However, both proteases and histamine contributed to calcium mobilization and extracellular signal-regulated kinase 1/2 activation. The nuclear translocation of nuclear factor-kappaB proteins was of greater magnitude in endothelial cells treated with the combination of mast cell granules and lipopolysaccharide. CONCLUSIONS:Mast cell granule serine proteases and histamine can amplify lipopolysaccharide-induced endothelial cell activation, which involves calcium mobilization, mitogen-activated protein kinase activation and nuclear factor-kappaB translocation.

Full Text

The Full Text of this article is available as a PDF (274.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aggarwal B. B. Tumour necrosis factors receptor associated signalling molecules and their role in activation of apoptosis, JNK and NF-kappaB. Ann Rheum Dis. 2000 Nov;59 (Suppl 1):i6–16. doi: 10.1136/ard.59.suppl_1.i6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arbabi S., Garcia I., Bauer G., Maier R. V. Hypertonic saline induces prostacyclin production via extracellular signal-regulated kinase (ERK) activation. J Surg Res. 1999 May 15;83(2):141–146. doi: 10.1006/jsre.1999.5583. [DOI] [PubMed] [Google Scholar]
  3. Arbabi S., Rosengart M. R., Garcia I., Maier R. V. Hypertonic saline solution induces prostacyclin production by increasing cyclooxygenase-2 expression. Surgery. 2000 Aug;128(2):198–205. doi: 10.1067/msy.2000.107606. [DOI] [PubMed] [Google Scholar]
  4. Baeuerle P. A., Baltimore D. I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science. 1988 Oct 28;242(4878):540–546. doi: 10.1126/science.3140380. [DOI] [PubMed] [Google Scholar]
  5. Berridge M. J., Lipp P., Bootman M. D. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol. 2000 Oct;1(1):11–21. doi: 10.1038/35036035. [DOI] [PubMed] [Google Scholar]
  6. Brand K., Page S., Walli A. K., Neumeier D., Baeuerle P. A. Role of nuclear factor-kappa B in atherogenesis. Exp Physiol. 1997 Mar;82(2):297–304. doi: 10.1113/expphysiol.1997.sp004025. [DOI] [PubMed] [Google Scholar]
  7. Chi L., Li Y., Stehno-Bittel L., Gao J., Morrison D. C., Stechschulte D. J., Dileepan K. N. Interleukin-6 production by endothelial cells via stimulation of protease-activated receptors is amplified by endotoxin and tumor necrosis factor-alpha. J Interferon Cytokine Res. 2001 Apr;21(4):231–240. doi: 10.1089/107999001750169871. [DOI] [PubMed] [Google Scholar]
  8. Chu Y., Solski P. A., Khosravi-Far R., Der C. J., Kelly K. The mitogen-activated protein kinase phosphatases PAC1, MKP-1, and MKP-2 have unique substrate specificities and reduced activity in vivo toward the ERK2 sevenmaker mutation. J Biol Chem. 1996 Mar 15;271(11):6497–6501. doi: 10.1074/jbc.271.11.6497. [DOI] [PubMed] [Google Scholar]
  9. Cotran R. S. American Association of Pathologists president's address. New roles for the endothelium in inflammation and immunity. Am J Pathol. 1987 Dec;129(3):407–413. [PMC free article] [PubMed] [Google Scholar]
  10. Cuenda A., Alessi D. R. Use of kinase inhibitors to dissect signaling pathways. Methods Mol Biol. 2000;99:161–175. doi: 10.1385/1-59259-054-3:161. [DOI] [PubMed] [Google Scholar]
  11. Dileepan K. N., Lorsbach R. B., Stechschulte D. J. Mast cell granules inhibit macrophage-mediated lysis of mastocytoma cells (P815) and nitric oxide production. J Leukoc Biol. 1993 Apr;53(4):446–453. doi: 10.1002/jlb.53.4.446. [DOI] [PubMed] [Google Scholar]
  12. Dileepan K. N., Simpson K. M., Stechschulte D. J. Modulation of macrophage superoxide-induced cytochrome c reduction by mast cells. J Lab Clin Med. 1989 May;113(5):577–585. [PubMed] [Google Scholar]
  13. Go Y. M., Levonen A. L., Moellering D., Ramachandran A., Patel R. P., Jo H., Darley-Usmar V. M. Endothelial NOS-dependent activation of c-Jun NH(2)- terminal kinase by oxidized low-density lipoprotein. Am J Physiol Heart Circ Physiol. 2001 Dec;281(6):H2705–H2713. doi: 10.1152/ajpheart.2001.281.6.H2705. [DOI] [PubMed] [Google Scholar]
  14. Gudmundsdóttir I. J., Halldórsson H., Magnúsdóttir K., Thorgeirsson G. Involvement of MAP kinases in the control of cPLA(2) and arachidonic acid release in endothelial cells. Atherosclerosis. 2001 May;156(1):81–90. doi: 10.1016/s0021-9150(00)00631-6. [DOI] [PubMed] [Google Scholar]
  15. Harlan J. M. Leukocyte-endothelial interactions. Blood. 1985 Mar;65(3):513–525. [PubMed] [Google Scholar]
  16. Himmel H. M., Whorton A. R., Strauss H. C. Intracellular calcium, currents, and stimulus-response coupling in endothelial cells. Hypertension. 1993 Jan;21(1):112–127. doi: 10.1161/01.hyp.21.1.112. [DOI] [PubMed] [Google Scholar]
  17. Ihara M., Urata H., Kinoshita A., Suzumiya J., Sasaguri M., Kikuchi M., Ideishi M., Arakawa K. Increased chymase-dependent angiotensin II formation in human atherosclerotic aorta. Hypertension. 1999 Jun;33(6):1399–1405. doi: 10.1161/01.hyp.33.6.1399. [DOI] [PubMed] [Google Scholar]
  18. Jehle A. B., Li Y., Stechschulte A. C., Stechschulte D. J., Dileepan K. N. Endotoxin and mast cell granule proteases synergistically activate human coronary artery endothelial cells to generate interleukin-6 and interleukin-8. J Interferon Cytokine Res. 2000 Apr;20(4):361–368. doi: 10.1089/107999000312298. [DOI] [PubMed] [Google Scholar]
  19. Jersmann H. P., Hii C. S., Ferrante J. V., Ferrante A. Bacterial lipopolysaccharide and tumor necrosis factor alpha synergistically increase expression of human endothelial adhesion molecules through activation of NF-kappaB and p38 mitogen-activated protein kinase signaling pathways. Infect Immun. 2001 Mar;69(3):1273–1279. doi: 10.1128/IAI.69.3.1273-1279.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kawaguchi Mio, Onuchic Luiz F., Huang Shau-Ku. Activation of extracellular signal-regulated kinase (ERK)1/2, but not p38 and c-Jun N-terminal kinase, is involved in signaling of a novel cytokine, ML-1. J Biol Chem. 2002 Mar 12;277(18):15229–15232. doi: 10.1074/jbc.C100641200. [DOI] [PubMed] [Google Scholar]
  21. Laine P., Kaartinen M., Penttilä A., Panula P., Paavonen T., Kovanen P. T. Association between myocardial infarction and the mast cells in the adventitia of the infarct-related coronary artery. Circulation. 1999 Jan 26;99(3):361–369. doi: 10.1161/01.cir.99.3.361. [DOI] [PubMed] [Google Scholar]
  22. Li Y., Chi L., Stechschulte D. J., Dileepan K. N. Histamine-induced production of interleukin-6 and interleukin-8 by human coronary artery endothelial cells is enhanced by endotoxin and tumor necrosis factor-alpha. Microvasc Res. 2001 May;61(3):253–262. doi: 10.1006/mvre.2001.2304. [DOI] [PubMed] [Google Scholar]
  23. Lin J. H., Zhu Y., Liao H. L., Kobari Y., Groszek L., Stemerman M. B. Induction of vascular cell adhesion molecule-1 by low-density lipoprotein. Atherosclerosis. 1996 Dec 20;127(2):185–194. doi: 10.1016/s0021-9150(96)05951-5. [DOI] [PubMed] [Google Scholar]
  24. Mantovani A., Sozzani S., Vecchi A., Introna M., Allavena P. Cytokine activation of endothelial cells: new molecules for an old paradigm. Thromb Haemost. 1997 Jul;78(1):406–414. [PubMed] [Google Scholar]
  25. Minden A., Lin A., McMahon M., Lange-Carter C., Dérijard B., Davis R. J., Johnson G. L., Karin M. Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. Science. 1994 Dec 9;266(5191):1719–1723. doi: 10.1126/science.7992057. [DOI] [PubMed] [Google Scholar]
  26. Molino M., Woolkalis M. J., Reavey-Cantwell J., Praticó D., Andrade-Gordon P., Barnathan E. S., Brass L. F. Endothelial cell thrombin receptors and PAR-2. Two protease-activated receptors located in a single cellular environment. J Biol Chem. 1997 Apr 25;272(17):11133–11141. doi: 10.1074/jbc.272.17.11133. [DOI] [PubMed] [Google Scholar]
  27. Muroi M., Muroi Y., Suzuki T. The binding of immobilized IgG2a to Fc gamma 2a receptor activates NF-kappa B via reactive oxygen intermediates and tumor necrosis factor-alpha 1. J Biol Chem. 1994 Dec 2;269(48):30561–30568. [PubMed] [Google Scholar]
  28. Muroi M., Muroi Y., Yamamoto K., Suzuki T. Influence of 3' half-site sequence of NF-kappa B motifs on the binding of lipopolysaccharide-activatable macrophage NF-kappa B proteins. J Biol Chem. 1993 Sep 15;268(26):19534–19539. [PubMed] [Google Scholar]
  29. Nystedt S., Ramakrishnan V., Sundelin J. The proteinase-activated receptor 2 is induced by inflammatory mediators in human endothelial cells. Comparison with the thrombin receptor. J Biol Chem. 1996 Jun 21;271(25):14910–14915. doi: 10.1074/jbc.271.25.14910. [DOI] [PubMed] [Google Scholar]
  30. Potente Michael, Michaelis U. Ruth, Fisslthaler Beate, Busse Rudi, Fleming Ingrid. Cytochrome P450 2C9-induced endothelial cell proliferation involves induction of mitogen-activated protein (MAP) kinase phosphatase-1, inhibition of the c-Jun N-terminal kinase, and up-regulation of cyclin D1. J Biol Chem. 2002 Feb 26;277(18):15671–15676. doi: 10.1074/jbc.M110806200. [DOI] [PubMed] [Google Scholar]
  31. Robinson A. J., Dickenson J. M. Activation of the p38 and p42/p44 mitogen-activated protein kinase families by the histamine H(1) receptor in DDT(1)MF-2 cells. Br J Pharmacol. 2001 Aug;133(8):1378–1386. doi: 10.1038/sj.bjp.0704200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Schumann R. R., Pfeil D., Lamping N., Kirschning C., Scherzinger G., Schlag P., Karawajew L., Herrmann F. Lipopolysaccharide induces the rapid tyrosine phosphorylation of the mitogen-activated protein kinases erk-1 and p38 in cultured human vascular endothelial cells requiring the presence of soluble CD14. Blood. 1996 Apr 1;87(7):2805–2814. [PubMed] [Google Scholar]
  33. Schwartz L. B., Irani A. M., Roller K., Castells M. C., Schechter N. M. Quantitation of histamine, tryptase, and chymase in dispersed human T and TC mast cells. J Immunol. 1987 Apr 15;138(8):2611–2615. [PubMed] [Google Scholar]
  34. Shimizu H., Mitomo K., Watanabe T., Okamoto S., Yamamoto K. Involvement of a NF-kappa B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines. Mol Cell Biol. 1990 Feb;10(2):561–568. doi: 10.1128/mcb.10.2.561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Smalley D. M., Lin J. H., Curtis M. L., Kobari Y., Stemerman M. B., Pritchard K. A., Jr Native LDL increases endothelial cell adhesiveness by inducing intercellular adhesion molecule-1. Arterioscler Thromb Vasc Biol. 1996 Apr;16(4):585–590. doi: 10.1161/01.atv.16.4.585. [DOI] [PubMed] [Google Scholar]
  36. Temkin Vladislav, Kantor Boris, Weg Vivian, Hartman Mor-Li, Levi-Schaffer Francesca. Tryptase activates the mitogen-activated protein kinase/activator protein-1 pathway in human peripheral blood eosinophils, causing cytokine production and release. J Immunol. 2002 Sep 1;169(5):2662–2669. doi: 10.4049/jimmunol.169.5.2662. [DOI] [PubMed] [Google Scholar]
  37. Umans J. G., Salvi D., Murray P. T., Wylam M. E. Selectivity of endotoxin-induced defect in endothelial calcium mobilization. Kidney Int. 1998 Oct;54(4):1063–1069. doi: 10.1046/j.1523-1755.1998.00090.x. [DOI] [PubMed] [Google Scholar]
  38. Vadas M. A., Gamble J. R., Rye K., Barter P. Regulation of leucocyte-endothelial interactions of special relevance to atherogenesis. Clin Exp Pharmacol Physiol. 1997 May;24(5):A33–A35. doi: 10.1111/j.1440-1681.1997.tb03052.x. [DOI] [PubMed] [Google Scholar]
  39. Wang Z., Jiang C., Ganther H., Lü J. Antimitogenic and proapoptotic activities of methylseleninic acid in vascular endothelial cells and associated effects on PI3K-AKT, ERK, JNK and p38 MAPK signaling. Cancer Res. 2001 Oct 1;61(19):7171–7178. [PubMed] [Google Scholar]
  40. Whitmarsh A. J., Davis R. J. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med (Berl) 1996 Oct;74(10):589–607. doi: 10.1007/s001090050063. [DOI] [PubMed] [Google Scholar]
  41. Worthen L. M., Nollert M. U. Intracellular calcium response of endothelial cells exposed to flow in the presence of thrombin or histamine. J Vasc Surg. 2000 Sep;32(3):593–601. doi: 10.1067/mva.2000.106955. [DOI] [PubMed] [Google Scholar]
  42. Zhang C., Kawauchi J., Adachi M. T., Hashimoto Y., Oshiro S., Aso T., Kitajima S. Activation of JNK and transcriptional repressor ATF3/LRF1 through the IRE1/TRAF2 pathway is implicated in human vascular endothelial cell death by homocysteine. Biochem Biophys Res Commun. 2001 Dec 7;289(3):718–724. doi: 10.1006/bbrc.2001.6044. [DOI] [PubMed] [Google Scholar]

Articles from Mediators of Inflammation are provided here courtesy of Wiley

RESOURCES