CD40-mediated immune-nonimmune cell interactions induce mucosal fibroblast chemokines leading to T-cell transmigration.
OBJECTIVE
The CD40 pathway is a key mediator of inflammation and autoimmunity. We investigated cell adhesion molecule (CAM) up-regulation and chemokine production by CD40-positive human intestinal fibroblasts (HIF) and microvascular endothelial cells (HIMEC) induced by CD40 ligand (CD40L)-positive T cells and soluble CD40L and their effect on T-cell adhesion and transmigration.


METHODS
Expression of CD40, CD40L, and CAM was assessed by immunohistochemistry, confocal microscopy and flow cytometric analysis, and chemokine production using enzyme-linked immunosorbent assay. Calcein-labeled T cells were used to assay HIF adhesion and Transwell HIMEC transmigration.


RESULTS
Ligation of CD40-positive HIF and HIMEC by CD40L-positive T cells or soluble CD40L induced up-regulation of CAM expression as well as interleukin-8 and RANTES production. The specificity of these responses was shown by inhibition with a CD40L blocking antibody and by CD40 signaling-dependent p38 mitogen-activated protein kinase phosphorylation. On CD40 ligation, HIF increased their T-cell binding capacity and generated chemoattractants able to induce T-cell migration through HIMEC monolayers.


CONCLUSIONS
Activation of the CD40/CD40L system in the gut mucosa may trigger a self-sustaining loop of immune-nonimmune cell interactions leading to an antigen-independent influx of T cells that contributes to chronic inflammation.
Vogel
Jon D
JD
Division of Gastroenterology, University Hospitals of Cleveland, Case Western University School of Medicine, Cleveland, OH 44106, USA.
West
Gail A
GA
Danese
Silvio
S
De La Motte
Carol
C
Phillips
Manijeh H
MH
Strong
Scott A
SA
Willis
Joseph
J
Fiocchi
Claudio
C
D019013:CD40 Antigens / Q000008:administration & dosage / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002450:Cell Communication; D002465:Cell Movement; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism*; D002630:Chemotactic Factors / Q000378:metabolism; D003106:Colon / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007107:Immune System / Q000503:physiopathology*; D015212:Inflammatory Bowel Diseases / Q000473:pathology / Q000503:physiopathology*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000098:blood supply; D008833:Microcirculation; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D013601:T-Lymphocytes / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D019013:CD40 Antigens; D015815:Cell Adhesion Molecules; D018925:Chemokines; D002630:Chemotactic Factors; D023201:CD40 Ligand; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases