Activated Platelets Are the Source of Elevated Levels of Soluble CD40 Ligand in the Circulation of Inflammatory Bowel Disease Patients

Overview

Journal Gut

Specialty Gastroenterology

Date 2003 Sep 13

PMID 12970136

Citations 94

Authors

S Danese

J A Katz

S Saibeni

A Papa

A Gasbarrini

M Vecchi

C Fiocchi

Affiliations

Soon will be listed here.

Abstract

Background: The CD40/CD40L system, a key regulator and amplifier of immune reactivity, is activated in inflammatory bowel disease (IBD) mucosa.

Aims: To determine whether plasma levels of sCD40L are elevated in Crohn's disease (CD) and ulcerative colitis (UC) patients compared with normal controls, to investigate the cellular source of sCD40L, and to explore CD40L induction mechanisms.

Patients: CD, UC, and normal control subjects were studied.

Methods: The concentration of sCD40L in plasma and supernatants of freshly isolated platelets and autologous peripheral blood T cells (PBT) was measured by ELISA. Surface CD40L expression level was measured by flow cytometry in resting and thrombin activated platelets, and unstimulated and CD3/CD28 stimulated PBT before and after coculture with human intestinal microvascular endothelial cells (HIMEC).

Results: Compared with normal controls, plasma sCD40L levels were significantly higher in both CD and UC patients and proportional to the extent of mucosal inflammation. Platelets from IBD patients displayed a significantly higher surface CD40L expression than those from control subjects, and released greater amounts of sCD40L than autologous PBT. Contact with IL-1beta activated HIMEC induced significant upregulation of CD40L surface expression and release by platelets.

Conclusions: Elevated levels of sCD40L in the circulation of IBD patients reflect enhanced surface expression and release of CD40L by platelets. This phenomenon translates to an increased platelet activation state apparently induced by passage through an inflamed mucosal microvascular bed, a conclusion supported by the positive correlation of plasma sCD40L levels with the extent of anatomical involvement by IBD. These results suggest that platelet-endothelial interactions critically contribute to activation of the CD40 pathway in IBD.

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References

Sutherland L, Martin F, Greer S, Robinson M, Greenberger N, Saibil F . 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology. 1987; 92(6):1894-8. DOI: 10.1016/0016-5085(87)90621-4. View

Harvey R, Bradshaw J . A simple index of Crohn's-disease activity. Lancet. 1980; 1(8167):514. DOI: 10.1016/s0140-6736(80)92767-1. View

Koizumi M, King N, LOBB R, Benjamin C, Podolsky D . Expression of vascular adhesion molecules in inflammatory bowel disease. Gastroenterology. 1992; 103(3):840-7. DOI: 10.1016/0016-5085(92)90015-q. View

Ware J, Heistad D . Seminars in medicine of the Beth Israel Hospital, Boston. Platelet-endothelium interactions. N Engl J Med. 1993; 328(9):628-35. DOI: 10.1056/NEJM199303043280907. View

Collins C, Cahill M, Newland A, Rampton D . Platelets circulate in an activated state in inflammatory bowel disease. Gastroenterology. 1994; 106(4):840-5. DOI: 10.1016/0016-5085(94)90741-2. View

Pietravalle F, Blasey H, Aubry J, Elson G, Edgerton M, Bonnefoy J . Human native soluble CD40L is a biologically active trimer, processed inside microsomes. J Biol Chem. 1996; 271(11):5965-7. DOI: 10.1074/jbc.271.11.5965. View

Collins C, Rampton D . Review article: platelets in inflammatory bowel disease--pathogenetic role and therapeutic implications. Aliment Pharmacol Ther. 1997; 11(2):237-47. DOI: 10.1046/j.1365-2036.1997.153328000.x. View

Binion D, West G, Ina K, Ziats N, Emancipator S, Fiocchi C . Enhanced leukocyte binding by intestinal microvascular endothelial cells in inflammatory bowel disease. Gastroenterology. 1997; 112(6):1895-907. DOI: 10.1053/gast.1997.v112.pm9178682. View

Klinger M . Platelets and inflammation. Anat Embryol (Berl). 1997; 196(1):1-11. DOI: 10.1007/s004290050075. View

10.

Kenny D, Newman P, Morateck P, Montgomery R . A dinucleotide deletion results in defective membrane anchoring and circulating soluble glycoprotein Ib alpha in a novel form of Bernard-Soulier syndrome. Blood. 1997; 90(7):2626-33. View

11.

Datta S, Kalled S . CD40-CD40 ligand interaction in autoimmune disease. Arthritis Rheum. 1997; 40(10):1735-45. DOI: 10.1002/art.1780401002. View

12.

Fiocchi C . Intestinal inflammation: a complex interplay of immune and nonimmune cell interactions. Am J Physiol. 1997; 273(4):G769-75. DOI: 10.1152/ajpgi.1997.273.4.G769. View

13.

Collins C, Rampton D, Rogers J, Williams N . Platelet aggregation and neutrophil sequestration in the mesenteric circulation in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 1998; 9(12):1213-7. View

14.

Schmitz G, Rothe G, Ruf A, Barlage S, Tschope D, Clemetson K . European Working Group on Clinical Cell Analysis: Consensus protocol for the flow cytometric characterisation of platelet function. Thromb Haemost. 1998; 79(5):885-96. View

15.

Fiocchi C . Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology. 1998; 115(1):182-205. DOI: 10.1016/s0016-5085(98)70381-6. View

16.

Slupsky J, Kalbas M, Willuweit A, Henn V, Kroczek R, Muller-Berghaus G . Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40. Thromb Haemost. 1998; 80(6):1008-14. View

17.

Vakkalanka R, Woo C, Kirou K, Koshy M, Berger D, Crow M . Elevated levels and functional capacity of soluble CD40 ligand in systemic lupus erythematosus sera. Arthritis Rheum. 1999; 42(5):871-81. DOI: 10.1002/1529-0131(199905)42:5<871::AID-ANR5>3.0.CO;2-J. View

18.

Aukrust P, Muller F, Ueland T, Berget T, Aaser E, Brunsvig A . Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation. 1999; 100(6):614-20. DOI: 10.1161/01.cir.100.6.614. View

19.

Liu Z, Colpaert S, dHaens G, Kasran A, de Boer M, Rutgeerts P . Hyperexpression of CD40 ligand (CD154) in inflammatory bowel disease and its contribution to pathogenic cytokine production. J Immunol. 1999; 163(7):4049-57. View

20.

Kato K, Rassenti L, Weisman M, Tamura N, Kobayashi S, Hashimoto H . The soluble CD40 ligand sCD154 in systemic lupus erythematosus. J Clin Invest. 1999; 104(7):947-55. PMC: 408556. DOI: 10.1172/JCI7014. View