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Synthetic fibronectin peptides interrupt inflammatory cell infiltration in transforming growth factor beta 1 knockout
K L Hines1, A B Kulkarni, J B McCarthy
1Cellular Immunology Section, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892.
Abstract:
Pronounced mononuclear leukocyte (MNL) infiltration occurs in multiple organs of mice homozygous for a transforming growth factor beta 1 (TGF-beta 1) loss-of-function gene mutation [TGF-beta 1 (-/-)], followed by cachexia and eventually death. Consistent with the increased leukocyte adhesion and tissue infiltration, MNLs isolated from spleen, thymus, and peripheral blood of symptomatic TGF-beta 1 (-/-) mice, as compared to littermate controls, exhibited increased adhesion to extracellular matrix proteins and to endothelial cells in vitro. Incubation of TGF-beta 1 (-/-) MNLs with selected synthetic peptides corresponding to cell- and heparin-binding sequences of fibronectin (FN) significantly attenuated adhesion of these cells not only to FN but also to endothelial cells in vitro. Based on these observations, mice were treated with the FN peptides in an attempt to rescue them from tissue inflammation and cardiopulmonary failure. Daily injections of a combination of four synthetic FN peptides that interact with beta 1-integrins and/or cell surface proteoglycans blocked the massive infiltration of MNLs into the heart and lungs of TGF-beta 1 (-/-) mice. Peptide treatment initiated on day 8, coincident with the first evidence of increased leukocyte-endothelial cell interactions, not only blocked tissue infiltration but also moderated the lethal wasting syndrome.
Insights
Transforming growth factor beta 1 (TGF-beta 1) deficiency causes severe inflammation and wasting in mice. Fibronectin peptides reduced leukocyte infiltration and moderated wasting, suggesting a therapeutic potential.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Transforming growth factor beta 1 (TGF-beta 1) loss-of-function mutation in mice leads to mononuclear leukocyte (MNL) infiltration, cachexia, and death.
- MNLs from affected mice show increased adhesion to extracellular matrix proteins and endothelial cells.
Purpose of the Study:
- To investigate the role of fibronectin (FN) interactions in MNL adhesion and tissue infiltration in TGF-beta 1 (-/-) mice.
- To evaluate the therapeutic potential of FN-derived peptides in mitigating inflammation and cachexia.
Main Methods:
- Isolation and in vitro adhesion assays of MNLs from TGF-beta 1 (-/-) mice and controls.
- Treatment of TGF-beta 1 (-/-) mice with a combination of four synthetic FN peptides targeting beta 1-integrins and proteoglycans.
- Monitoring of leukocyte infiltration, tissue inflammation, and wasting syndrome.
Main Results:
- Synthetic FN peptides significantly attenuated MNL adhesion to FN and endothelial cells in vitro.
- Daily FN peptide injections blocked massive MNL infiltration into the heart and lungs of TGF-beta 1 (-/-) mice.
- Peptide treatment initiated early in disease onset moderated the lethal wasting syndrome.
Conclusions:
- Fibronectin-mediated leukocyte adhesion is a critical factor in the pathogenesis of TGF-beta 1 deficiency-induced inflammation.
- Targeting fibronectin interactions with synthetic peptides offers a promising therapeutic strategy for inflammatory diseases and cachexia.