Critical role of the CD40 CD40-ligand pathway in regulating mucosal inflammation-driven angiogenesis in inflammatory bowel disease.
OBJECTIVE
Angiogenesis is a novel component in inflammatory bowel disease (IBD) pathogenesis. We have previously shown that immune-nonimmune interactions through the CD40-CD40-ligand (CD40L) pathway might sustain gut inflammation, although their effect on regulating inflammation-driven angiogenesis is unknown. The present study evaluated the role of the CD40-CD40L interaction in the promotion of immune-mediated angiogenesis in IBD.


METHODS
Human nonimmune cells of colonic origin-namely, human intestinal fibroblasts (HIFs) and human intestinal microvascular endothelial cells (HIMECs)-were activated with either soluble CD40L (sCD40L), or CD40(+) D1.1 cells or CD40L-activated lamina propria T (LPT) cells before measuring pro-angiogenic cytokine release. Blocking antibodies to either CD40 or CD40L were used to disrupt the CD40-CD40L interaction. The dextran sodium sulphate (DSS) model of experimental colitis in CD40 and CD40L knockout mice was established to assess whether the CD40-CD40L pathway was implicated in controlling inflammation-driven angiogenesis in vivo.


RESULTS
Engagement of CD40 on HIFs promoted the release of vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and hepatocyte growth factor (HGF). LPT cells were potent inducers of pro-angiogenic cytokine secretion by HIFs. Supernatants from sCD40L-activated HIFs induced migration of HIMECs and tubule formation, both of which were inhibited by blocking antibodies to either VEGF, IL-8 or HGF. Both CD40- and CD40L-deficient mice were protected from DSS-induced colitis and displayed a significant impairment of gut inflammation-driven angiogenesis, as assessed by microvascular density.


CONCLUSIONS
The CD40-CD40L pathway appears to be crucially involved in regulating inflammation-driven angiogenesis, suggesting that strategies aimed at blocking CD40-CD40L interactions might be beneficial in acute and chronic intestinal injury.
Danese
S
S
Division of Gastroenterology, Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Milan, Italy. sdanese@hotmail.com
Scaldaferri
F
F
Vetrano
S
S
Stefanelli
T
T
Graziani
C
C
Repici
A
A
Ricci
R
R
Straface
G
G
Sgambato
A
A
Malesci
A
A
Fiocchi
C
C
Rutella
S
S
D000818:Animals; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003092:Colitis / Q000276:immunology; D003106:Colon / Q000276:immunology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology; D005347:Fibroblasts / Q000276:immunology; D017228:Hepatocyte Growth Factor / Q000032:analysis; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D016209:Interleukin-8 / Q000032:analysis; D007413:Intestinal Mucosa / Q000098:blood supply / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D019013:CD40 Antigens; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D023201:CD40 Ligand; D017228:Hepatocyte Growth Factor