Platelets trigger a CD40-dependent inflammatory response in the microvasculature of inflammatory bowel disease patients.
OBJECTIVE
Platelets circulate in an activated state in patients with inflammatory bowel disease (IBD), but their role in the pathogenesis of IBD is unclear. The recent demonstration that activated platelets express CD40 ligand (L) provides a mechanism of interaction with CD40-positive endothelial cells, inducing them to produce proinflammatory mediators. We investigated whether platelets from patients with IBD express enhanced levels of CD40L and induce human intestinal microvascular endothelial cells (HIMEC) to up-regulate cell adhesion molecule (CAM) expression and secrete chemokines.


METHODS
CD40L expression was assessed in resting and thrombin-activated platelets by flow cytometry and in mucosal microthrombi by confocal microscopy. Platelet-HIMEC cocultures were used to study CAM up-regulation, and interleukin (IL)-8 and RANTES production by HIMEC.


RESULTS
IBD platelets expressed significantly higher CD40L levels than those of healthy subjects, and CD40L-positive platelets were detected in IBD-involved mucosa. Activated platelets up-regulated expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 as well as production of interleukin 8 by HIMEC in a CD40-dependent fashion. High levels of RANTES were present in platelet-HIMEC cocultures and platelets were identified as the source of this chemokine, which mediated T-cell adhesion to HIMEC.


CONCLUSIONS
These results show that platelets can actively contribute to mucosal inflammation and represent a previously unrecognized component of IBD pathogenesis.
Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Ohio 44106, USA.
Silvio
S
Danese
Carol
C
de la Motte
Andreas
A
Sturm
Jon D
JD
Vogel
Gail A
GA
West
Scott A
SA
Strong
Jeffry A
JA
Katz
Claudio
C
Fiocchi
D001792:Blood Platelets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism*; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000209:etiology / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology; D008833:Microcirculation / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010974:Platelet Aggregation; D013601:T-Lymphocytes / Q000166:cytology; D015854:Up-Regulation / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D019013:CD40 Antigens; D018946:Chemokine CCL5; D016209:Interleukin-8; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases