Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12-dependent emphysema.

Abstract

Integrins are heterodimeric cell-surface proteins that regulate cell growth, migration and survival. We have shown previously that the epithelial-restricted integrin alpha(v)beta6 has another critical function; that is, it binds and activates latent transforming growth factor-beta (TGF-beta). Through a global analysis of pulmonary gene expression in the lungs of mice lacking this integrin (Itgb6 null mice) we have identified a marked induction of macrophage metalloelastase (Mmp12)--a metalloproteinase that preferentially degrades elastin and has been implicated in the chronic lung disease emphysema. Here we report that Itgb6-null mice develop age-related emphysema that is completely abrogated either by transgenic expression of versions of the beta6 integrin subunit that support TGF-beta activation, or by the loss of Mmp12. Furthermore, we show that the effects of Itgb6 deletion are overcome by simultaneous transgenic expression of active TGF-beta1. We have uncovered a pathway in which the loss of integrin-mediated activation of latent TGF-beta causes age-dependent pulmonary emphysema through alterations of macrophage Mmp12 expression. Furthermore, we show that a functional alteration in the TGF-beta activation pathway affects susceptibility to this disease.

• Authors: David G Morris, Xiaozhu Huang, Naftali Kaminski, Yanli Wang, Steven D Shapiro, Gregory Dolganov, Adam Glick, Dean Sheppard
• Journal: Nature (Nature) Vol. 422 Issue 6928 Pg. 169-73 (Mar 13 2003) ISSN: 0028-0836 [Print] England
• PMID: 12634787 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antigens, Neoplasm
• Integrin beta Chains
• Integrins
• Transforming Growth Factor beta
• integrin alphavbeta6
• integrin beta6
• Metalloendopeptidases
• MMP12 protein, human
• Matrix Metalloproteinase 12

Topics

• Aging
• Animals
• Antigens, Neoplasm (genetics, metabolism)
• Disease Progression
• Disease Susceptibility
• Gene Deletion
• Humans
• Inflammation (enzymology, genetics, metabolism)
• Integrin beta Chains (genetics, metabolism)
• Integrins (genetics, metabolism)
• Macrophages, Alveolar (enzymology)
• Matrix Metalloproteinase 12
• Metalloendopeptidases (genetics, metabolism)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Pulmonary Emphysema (enzymology, genetics, metabolism)
• Transforming Growth Factor beta (genetics, metabolism)