Critical role of the CD40-CD40 ligand pathway in governing mucosal inflammation-driven angiogenesis in inflammatory bowel disease

Silvio Danese ^1*, Franco Scaldaferri ², Stefania Vetrano ¹, Tommaso Stefanelli ¹, Cristina Graziani ², Alessandro Repici ¹, Riccardo Ricci ², Alessandro Sgambato ², Giuseppe Straface ², Alberto Malesci ¹, Claudio Fiocchi ³ and Sergio Rutella ²

¹ Istituto Clinico Humanitas, Italy
² Università Cattolica, Italy
³ Cleveland Clinic, United States

^* To whom correspondence should be addressed. E-mail: sdanese{at}hotmail.com.

Accepted 13 February 2007

Abstract

Background and aims: 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 in governing 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 (HIF) and human intestinal microvascular endothelial cells (HIMEC), were activated with either soluble CD40 ligand (sCD40L), or CD40+ D1.1 cells or CD40L-activated lamina propria T cells (LPT) before measuring pro-angiogenic cytokine release. Blocking antibodies to either CD40 or CD40L were used to disrupt the CD40-CD40L interaction. The DSS model of experimental colitis in CD40 and CD40L knock-out mice was established to assess whether the CD40-CD40L pathway was implicated in controlling inflammation-driven angiogenesis in vivo.

Results: Engagement of CD40 on HIF promoted VEGF, IL-8 and HGF release. LPT cells were potent inducers of pro-angiogenic cytokine secretion by HIF. Supernatants from sCD40L-activated HIF induced migration of HIMEC and tubule formation both of which were inhibited by blocking antibodies to either VEGF or 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 CD40L-CD40 interactions might be beneficial in acute and chronic intestinal injury.

Keywords: CD40, IBD, angiogenesis, endothelium

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