IL-17 promotes p38 MAPK-dependent endothelial activation enhancing neutrophil recruitment to sites of inflammation.

Abstract

Neutrophilic inflammation plays an important role in lung tissue destruction occurring in many chronic pulmonary diseases. Neutrophils can be recruited to sites of inflammation via the action of the cytokine IL-17. In this study, we report that IL-17RA and IL-17RC mRNA expression is significantly increased in asthmatic bronchoscopic biopsies and that these receptors are not only expressed on epithelial and inflammatory cells but also on endothelial cells. IL-17 potently stimulates lung microvascular endothelial cells to produce chemoattractants (CXCL8 and derivatives of the 5-lipoxygenase pathway) that selectively drive neutrophil but not lymphocyte chemotaxis. Moreover, IL-17 promotes endothelial activation by inducing the expression of endothelial adhesion markers (E-selectin, VCAM-1, and ICAM-1) in a p38 MAPK-dependent manner. This increased expression of adhesion molecules stimulates the trans-endothelial migration of neutrophils, as well as the transmigration of HT-29 colon carcinoma cells, suggesting a further role in promoting lung metastasis. Finally, IL-17 increased neutrophil adhesion to the endothelium in vivo as determined by intravital microscopy of mice cremaster muscle. Overall, our results demonstrate that IL-17 is a potent activator of the endothelium in vivo leading to neutrophil infiltration. Therefore, preventing neutrophil recruitment by blocking the action of IL-17 on endothelial cells may prove to be highly beneficial in diseases in which neutrophilic inflammation plays a key role.

• Authors: Lucie Roussel, François Houle, Carlos Chan, Yu Yao, Julie Bérubé, Ron Olivenstein, James G Martin, Jacques Huot, Qutayba Hamid, Lorenzo Ferri, Simon Rousseau
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 184 Issue 8 Pg. 4531-7 (Apr 15 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20228195 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CXCL8 protein, human
• IL17A protein, human
• Inflammation Mediators
• Interleukin-17
• Interleukin-8
• p38 Mitogen-Activated Protein Kinases

Topics

• Adult
• Animals
• Asthma (immunology, metabolism, pathology)
• Cells, Cultured
• Endothelium, Vascular (enzymology, immunology, metabolism, pathology)
• HT29 Cells
• Humans
• Inflammation (enzymology, immunology, pathology)
• Inflammation Mediators (physiology)
• Interleukin-17 (biosynthesis, physiology)
• Interleukin-8 (biosynthesis)
• Jurkat Cells
• MAP Kinase Signaling System (immunology)
• Male
• Mice
• Neutrophil Infiltration (immunology)
• Neutrophils (enzymology, immunology, pathology)
• p38 Mitogen-Activated Protein Kinases (physiology)