Allograft Inflammatory Factor-1 in Cardiac Ischemia Re-perfusion Injury: Release of Molecular Markers in an in Vitro Setting


Initial ischemia/reperfusion injury (IRI) may have an impact on recipient immune responses after transplantation. Allograft inflammatory factor-1 (AIF-1) has been implicated in the regulation of inflammation associated with organ rejection. We hypothesized that it is either passively released from injured tissues during organ procurement, or actively secreted by allograft infiltrating cells contributing to allograft dysfunction. We investigated the impact of IRI in an in vitro study of human heart tissue during the process of transplantation. The mRNA expression levels for both isoforms of the AIF-1, I2 and I3 were significantly increased after 30 minutes reperfusion (AIF-1 I2: p < 0.01 vs. AIF-1 I3: p < 0.005). Expression levels for IL-18 and the TLRs were increased after 30 minutes of reperfusion. Only IL-18 and TLR-2 were statistically significant (IL-18: p < 0.0001 vs. TLR-2: p < 0.01). The mRNA expression levels for AIF-1 I2 and IL-18 were decreased from the original levels of ischemia after 60 and 90 minutes reperfusion. The TLR-2 and -4 were presented with minimal levels of reduction after 60 minutes. However, mRNA expression levels for all were decreased to the original levels of ischemia after 90 minutes, except for AIF-1 I3, but the difference was not statistically significant. AIF-1 and IL-18 were specifically detected in myocytes and interstitial tissues by immunohistochemistry (IHC) stain after IRI. TLR-4 was non-specific, and TLR2 was minimally expressed. The study discusses the evidence supporting that the AIF-1 may have therapeutic potential for strategies in the control of innate immune responses early on, after transplantation.

Share and Cite:

McDaniel, D. , Zhou, X. , Rigney, D. , McDaniel, L. , Aru, G. , Tribble, C. , Creswell, L. and Merrill, W. (2013) Allograft Inflammatory Factor-1 in Cardiac Ischemia Re-perfusion Injury: Release of Molecular Markers in an in Vitro Setting. Open Journal of Organ Transplant Surgery, 3, 5-12. doi: 10.4236/ojots.2013.31002.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] W. G. Land, “Innate Immunity-Mediated Allograft Rejection and Strategies to Prevent It,” Transplantation Proceedings, Vol. 39, No. 3, 2007, pp. 667-672. doi:10.1016/j.transproceed.2007.01.052
[2] J. Gurevitch, I. Frolkis and Y. Yuhas, “Tumor Necrosis-Alpha Is Released from the Isolated Heart Undergoing Ischemia and Reperfusion,” The American College of Cardiology, Vol. 28, No. 1, 1966, pp. 247-252. doi:10.1016/0735-1097(96)00105-2
[3] D. M. Yellon and D. J. Hausenloy, “Mechanisms of Disease: Myocardial Reperfusion Injury,” The New England Journal of Medicine, Vol. 357, No. 9, 2007, pp. 1121-1135. doi:10.1056/NEJMra071667
[4] W. G. Land, “The Role of Postischemic Reperfusion Injury and Other Nonantigen-Dependent Inflammatory Pathways in Transplantation,” Transplantation, Vol. 79, No. 5, 2005, pp. 505-514. doi:10.1097/01.TP.0000153160.82975.86
[5] J. M. Downey, “Free Radicals and Their Involvement during Long-Term Myocardial Ischemia and Reperfusion,” Annual Review Physiology, Vol. 52, 1990, pp. 487-504.
[6] E. Noiri, A. Nakao, K. Uchida, et al., “Oxidative and Nitrosative Stress in Acute Renal Ischemia,” American Journal of Physiological Renal Physiology, Vol. 281, No. 5, 2001, pp. F948-F957.
[7] J. T. Flaherty, B. Pitt, J. W. Gruber, et al., “Recombinant Human Superoxide Dismutase (h-SOD) Fails to Improve Recovery of Ventricular Function in Patients Undergoing Coronary Angioplasty for Acute Myocardial Infarction,” Circulation, Vol. 89, No. 5, 1994, pp. 1982-1991. doi:10.1161/01.CIR.89.5.1982
[8] W. G. Land, “Emerging role of Innate Immunity in Organ Transplantation Part II: Potential of Damage-Associated Molecular Patterns to Generate Immunostimulatory Dendritic Cells,” Transplantation Reviews, Vol. 26, No. 2, 2012, pp. 73-87. doi:10.1016/j.trre.2011.02.003
[9] G. Liu, H. Ma, L. Jiang and Y. Zhao, “Allograft Inflammatory Factor-1 and Its Immune Regulation,” Autoimmunity, Vol. 40, No. 2, 2007, pp. 95-102. doi:10.1080/08916930601083946
[10] F. Del Galdo and S. A. Jimenez, “T Cell Expressing Allograft Inflammatory Factor-1 Display Increases Chemotaxis and Induce a Pro-Fibrotic Phenotype in Normal Fibroblasts in vitro,” Arthritis Rheumatism, Vol. 56, No. 10, 2007, pp. 3478-3488. doi:10.1002/art.22877
[11] U. Utans, R. J. Arceci, Y. Yamashita and M. E. Russell, “Cloning and Characterization of Allograft Inflammatory Factor-1: A Novel Macrophage Factor Identified in Rat Cardiac Allografts with Chronic Rejection,” Journal of Clinical Investigation, Vol. 95, No. 5, 1995, pp. 2954-2962. doi:10.1172/JCI118003
[12] U. Utans, W. C. Quist, B. M. McManus, J. E. Wilson and R. J. Arceci, “Allograft Inflammatory Factor-1. A Cytokine Responsive Macrophage Molecule Expressed in Transplanted Human Hearts,” Transplantation, Vol. 61, No. 9, 1996, pp. 1387-1392. doi:10.1097/00007890-199605150-00018
[13] S. E. Kelemen and M. V. Autieri, “Expression of Allograft Inflammatory Factor-1 in T Lymphocytes: A Role in T-Lymphocyte Activation and Proliferative Arteriopathies,” American Journal of Pathology, Vol. 167, No. 2, 2005, pp. 619-626. doi:10.1016/S0002-9440(10)63003-9
[14] M. V. Autieri, C. Carbone and A. Mu, “Expression of Allograft Inflammatory Factor-1 Is a Marker of Activation Human Vascular Smooth Muscle Cells and Arterial Injury,” Arteriosclerosis Thrombosis Vascular Biology, Vol. 20, No. 7, 2000, pp. 1737-1744. doi:10.1161/01.ATV.20.7.1737
[15] M. H. Deininger, K. Seid, S. Engel, R. Meyermann and H. J. Schluesener, “Allograft Inflammatory Factor-1 Defines a Distinct Subset of Infiltrating Macrophages/microglial cells in Rat and Human Gliomas,” Acta Neurophathology, Vol. 100, No. 6, 2000, pp. 673-680. doi:10.1007/s004010000233
[16] Y. Tian, S. Jain, S. E. Kelemen and M. V. Autieri, “AIF-1 Expression Regulates Endothelial Cell Activation, Signal Transduction, and Vasculogenesis,” American Journal of Physiology Cell Physiology, Vol. 296, No. 2, 2009, pp. C256-C266. doi:10.1152/ajpcell.00325.2008
[17] R. Kuschel, M. H. Deininger, R. Meyermann, A. Bornemann, Z. Yablonka-Reuveni and H. J. Schluesener, “Allograft Inflammatory Factor-1 Is Expressed by Macrophages in Injured Skeletal Muscle and Abrogates Proliferation and Differentiation of Satellite Cells,” Journal of Neurophatology Experimental Neurology, Vol. 59, No. 4, 2000, pp. 323-332.
[18] C. Orsmark, T. Skoog, L. Jeskanen, J. Kere and U. Saarialho-Kere, “Expression of Allograft Inflammatory Factor-1 in Inflammatory Skin Disorders,” Acta Dermato-Venereologica, Vol. 87, No. 3, 2007, pp. 223-227.
[19] T. C. Lund, L. B. Anderson, V. McCullar, et al., “iTRAQ Is a Useful Method to Screen for Membrane-Bound Proteins Differentially Expressed in Human Natural Killer Cell Types,” Journal of Proteome Research, Vol. 6, No. 2, 2007, pp. 644-653. doi:10.1021/pr0603912
[20] Y. Tsubata, M. Sakatsume, A. Ogawa, et al., “Expression of Allograft Inflammatory Factor-1 in Kidneys: A Novel Molecular Component of Podocyte,” Kidney International, Vol. 70, No. 11, 2006, pp. 1948-1954.
[21] C. Kohler, “Allograft Inflammatory Factor-1/Ionized Calcium-binding Adapter Molecule 1 Is Specifically Expressed by most Subpopulations of Macrophages and Spermatids in Testis,” Cell and Tissue Research, Vol. 330, No. 2, 2007, pp. 291-302. doi:10.1007/s00441-007-0474-7
[22] D. O. Taylor, L. B. Edwards, M. M. Boucek, et al., “Registry of the International Society for Heart and Lung Transplantation: Twenty-second Official Adult Heart Transplant Report, 2005,” Journal of Heart Lung Transplantation, Vol. 24, No. 8, 2005, pp. 945-955. doi:10.1016/j.healun.2005.05.018
[23] X. Zhou, Z. He, J. Henegar, B. Allen and S. Bigler, “Expression of Allograft Inflammatory Factor-1 (AIF-1) in Acute Cellular Rejection of Cardiac Allografts,” Cardiovascular Pathology, Vol. 20, No. 5, 2011, pp. e177-e184. doi:10.1016/j.carpath.2010.08.002
[24] A. K. Barker, D. O. McDaniel, X. Zhou, et al., “Combined Analysis of Allograft Inflammatory Factor-1, Interleukin-18, and Toll-Like Receptor Expression and Association with Allograft Rejection and Coronary Vasculopathy,” The American Surgeon, Vol. 76, No. 8, 2010, pp. 872-878.
[25] A. M. Sheridan and J. V. Bonventre, “Cell Biology and Molecular Mechanisms of Injury in Ischemic Acute Renal Failure,” Current Opinion Nephrology Hypertension, Vol. 9, No. 4, 2000, pp. 427-434. doi:10.1097/00041552-200007000-00015
[26] D. J. Kaczorowski, A. Tsung and T. R. Billiar, “Innate Immune Mechanisms in Ischemia/Reperfusion,” Frontiers Bioscience, Vol. 1, No. 6, 2009, pp. 91-98.
[27] M. Takahashi, “Role of the Inflammasome in Myocardial Infarction,” Trends in Cardiovascular Medicine, Vol. 21, No. 2, 2011, pp. 37-41. doi:10.1016/j.tcm.2012.02.002
[28] M. V. Autieri, S. Kelemen, B. A. Thomas, E. D. Feller, B. I. Goldman and H. J. Eisen, “Allograft Inflammatory Factor-1 Expression Correlates with Cardiac Rejection and Development of Cardiac Allograft Vasculopathy,” Circulation, Vol. 106, No. 17, 2002, pp. 2218-2223. doi:10.1161/01.CIR.0000035652.71915.00
[29] D. O. McDaniel, X. Zhou, C. K. Moore and G. Aru, “Cardiac Allograft Rejection Correlates with Increased Expressions of Toll-like Receptor 2 and 4 and Allograft Inflammatory Factor 1,” Transplantation Proceedings, Vol. 42, No. 10, 2010, pp.5235-4237. doi:10.1016/j.transproceed.2010.09.091
[30] Z. F. Yang, D. W. Ho, C. K. Lau, et al., “Allograft Inflammatory Factor-1 (AIF-1) Is Crucial for the Survival and Pro-Inflammatory Activity of Macrophages,” International Immunology, Vol. 17, No. 11, 2005, pp. 1391- 1397. doi:10.1093/intimm/dxh316
[31] Y. Tian, S. E. Kelemen and M. V. Autieri, “Inhibition of AIF-1 Expression by Constitutive siRNA Expression Reduces Macrophage Migration, Proliferation, and Signal Transduction Initiated by Atherogenic Stimuli,” American Journal of Physiology Cell Physiology, Vol. 290, No. 4, 2006, pp. C1083-C1091. doi:10.1152/ajpcell.00381.2005
[32] Y. Nagakawa, S. Nomoto, Y. Kato, et al., “Over-Expression of AIF-1 in Liver Allograft and Peripheral Blood Correlates with Acute Rejection after Transplantation in Rats,” American Journal of Transplantation, Vol. 4, No. 12, 2004, pp. 1949-1957. doi:10.1111/j.1600-6143.2004.00621.x
[33] W. Jiang, L. Kong, X. Wu and X. Wang, “Allograft Inflammatory Factor-1 Is Up-Regulated in Warm and Cold Ischemia-Reperfusion Injury in Rat Liver and May Be Inhibited by FK506,” Journal of Surgical Research, Vol. 165, No. 1, 2011, pp. 158-164. doi:10.1016/j.jss.2009.05.038
[34] E. Antiga, W. Volpi, D. Torchia, P. Fabbri and M. Caproni, “Effects of Tacrolimus Ointment on Toll-Like Receptors in Atopic Dermatitis,” Clinical Experimental Dermatology, Vol. 36, No. 3, 2011, pp. 235-241. doi:10.1111/j.1365-2230.2010.03948.x
[35] A. Gluba, M. Banach, S. Hannam, D. P. Mikhailidis, A. Sakowicz and J. Rysz, “The Role of Toll-Like Receptor in Renal Diseases,” Nature Review Nephrology, Vol. 6, No. 4, 2010, pp. 224-235. doi:10.1038/nrneph.2010.16
[36] D. R. Goldstein, “Toll Like Receptors and Acute Allograft Rejection,” Transplant Immunology, Vol. 17, No. 1, 2006, pp. 11-15. doi:10.1016/j.trim.2006.09.012
[37] C. A. Farrar, B. Keogh, W. McCormack, et al., “Inhibition of TLR2 Promotes Graft Function in a Murine Model of Renal Transplant Ischemia-Reperfusion Injury,” Federation American Society Experimental Biology Journal, Vol. 26, No. 2, 2012, pp. 799-807.
[38] F. Arslan, M. B. Smeets, A. A. O’Neill, et al., “Myocardial Ischemia/Reperfusion Injury Is Mediated by Leukocytic Toll-like Receptor-2 and Reduced by Systemic Administration of a Novel Anti-Toll-like Receptor-2 Antibody,” Circulation, Vol. 121,No. 1, 2010, pp. 80-90. doi:10.1161/CIRCULATIONAHA.109.880187
[39] S. Frantz, L. Kobzik, K. Young-Dae, et al., “Toll4 (TLR4) Expression in Cardiac Myocytes in Normal and Failing Myocardium,” Journal of Clinical Investigation, Vol. 104, No. 3, 1999, pp. 271-280. doi:10.1172/JCI6709

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.