This Article Order Full text via Infotrieve Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Coito, A. J. Articles by van de Water, L. Search for Related Content PubMed PubMed Citation Articles by Coito, A. J. Articles by van de Water, L.

American Journal of Pathology, Vol 150, 1757-1772, Copyright © 1997 by American Society for Investigative Pathology

REGULAR ARTICLES

Expression of fibronectin splicing variants in organ transplantation: a differential pattern between rat cardiac allografts and isografts

AJ Coito, LF Brown, JH Peters, JW Kupiec-Weglinski and L van de Water
Department of Pathology, Beth Israel Hospital, Boston, Massachusetts, USA.

Allograft rejection is associated with infiltration of inflammatory cells and deposition of extracellular matrix proteins. The extent to which diversity in the extracellular matrix regulates inflammatory cell function in transplants remains unclear. One group of extracellular matrix proteins, termed fibronectins (FNs), exhibits inherent diversity as a consequence of alternative splicing in three segments: EIIIA, EIIIB, or V. Although the EIIIA segment has documented functions in mesenchymal cell differentiation, neither this segment nor the EIIIB segment have been tested for effects specific to leukocyte functions. By contrast, the V region can include the CS-1 segment to which leukocytes may adhere through alpha 4 beta 1 integrins. In this study, we demonstrate that EIIIA+, EIIIB+, and V+ FN variants are synthesized, primarily by macrophages in distinct temporal and spatial patterns in two rat cardiac transplant models: either with antigenic challenge, allografts, or without challenge, isografts. The ratio of EIIIA inclusion into FN increases by day 1 in allografts and isografts and remains high until allografts are rejected (approximately 7 days) but falls to normal levels in tolerated isografts (day 6). EIIIB+ FN ratios in allografts peak later than do EIIIA+ FNs (day 4). EIIIB+ FN ratios remain relatively low in isografts. Interestingly, EIIIA+ and EIIIB+ FNs are deposited prominently in the myocardium of rejecting allografts in close association with infiltrating leukocytes, and FN expression and deposition are prominent at sites of infarction. By contrast, these FNs are largely restricted to the epicardium and to a lesser degree in the immediately adjacent myocardium in isografts. CS-1+ FNs increase in allografts and isografts at 3 hours after transplantation but are particularly prominent in allografts 1 to 3 days before rejection. Our data suggest that FN splicing variants have a differential role in the effector functions of leukocytes in allografts and isografts and provide a foundation for testing their function on leukocytes and a rationale for FN-based therapeutics to modulate allograft rejection in transplant recipients.

This article has been cited by other articles:

				A. V. Shinde, C. Bystroff, C. Wang, M. G. Vogelezang, P. A. Vincent, R. O. Hynes, and L. Van De Water Identification of the Peptide Sequences within the EIIIA (EDA) Segment of Fibronectin That Mediate Integrin {alpha}9{beta}1-dependent Cellular Activities J. Biol. Chem., February 1, 2008; 283(5): 2858 - 2870. [Abstract] [Full Text] [PDF]

				C. Moore, X.-D. Shen, F. Gao, R. W. Busuttil, and A. J. Coito Fibronectin-{alpha}4{beta}1 Integrin Interactions Regulate Metalloproteinase-9 Expression in Steatotic Liver Ischemia and Reperfusion Injury Am. J. Pathol., February 1, 2007; 170(2): 567 - 577. [Abstract] [Full Text] [PDF]

				M. H. Tan, Z. Sun, S. L. Opitz, T. E. Schmidt, J. H. Peters, and E. L. George Deletion of the alternatively spliced fibronectin EIIIA domain in mice reduces atherosclerosis Blood, July 1, 2004; 104(1): 11 - 18. [Abstract] [Full Text] [PDF]

				T. Hattori, H. Shimokawa, M. Higashi, J. Hiroki, Y. Mukai, K. Kaibuchi, and A. Takeshita Long-Term Treatment With a Specific Rho-Kinase Inhibitor Suppresses Cardiac Allograft Vasculopathy in Mice Circ. Res., January 9, 2004; 94(1): 46 - 52. [Abstract] [Full Text] [PDF]

				R. M. Klein, M. Zheng, A. Ambesi, L. Van De Water, and P. J. McKeown-Longo Stimulation of extracellular matrix remodeling by the first type III repeat in fibronectin J. Cell Sci., November 15, 2003; 116(22): 4663 - 4674. [Abstract] [Full Text] [PDF]

				F. Amersi, X.-D. Shen, C. Moore, J. Melinek, R. W. Busuttil, J. W. Kupiec-Weglinski, and A. J. Coito Fibronectin-{alpha}4{beta}1 Integrin-Mediated Blockade Protects Genetically Fat Zucker Rat Livers from Ischemia/Reperfusion Injury Am. J. Pathol., April 1, 2003; 162(4): 1229 - 1239. [Abstract] [Full Text] [PDF]

				Y.-F. Liao, P. J. Gotwals, V. E. Koteliansky, D. Sheppard, and L. Van De Water The EIIIA Segment of Fibronectin Is a Ligand for Integrins alpha 9beta 1 and alpha 4beta 1 Providing a Novel Mechanism for Regulating Cell Adhesion by Alternative Splicing J. Biol. Chem., April 19, 2002; 277(17): 14467 - 14474. [Abstract] [Full Text] [PDF]

				A. J. Coito, K. Onodera, H. Kato, R. W. Busuttil, and J. W. Kupiec-Weglinski Fibronectin-Mononuclear Cell Interactions Regulate Type 1 Helper T Cell Cytokine Network in Tolerant Transplant Recipients Am. J. Pathol., October 1, 2000; 157(4): 1207 - 1218. [Abstract] [Full Text] [PDF]

				Y.-F. Liao, K. G. Wieder, J. M. Classen, and L. V. De Water Identification of Two Amino Acids within the EIIIA (ED-A) Segment of Fibronectin Constituting the Epitope for Two Function-blocking Monoclonal Antibodies J. Biol. Chem., June 18, 1999; 274(25): 17876 - 17884. [Abstract] [Full Text] [PDF]