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• W2028628211 abstract "T-cell-mediated renal injury is a major cause of kidney transplant rejection and renal failure; hence, understanding T-cell migration within the kidney is important for preventing renal injury. Interleukin (IL)-16 is a T-cell chemoattractant produced by leukocytes. Here we measured IL-16 expression in the kidney and its role in renal ischemia–reperfusion injury induced by different conditions in several strains of mice. IL-16 was strongly expressed in distal and proximal straight tubules of the kidney. The IL-16 precursor protein was cleaved to a chemotactic form in cultured tubular epithelial cells. Inactivation of IL-16 by antibody therapy or IL-16 deficiency prevented ischemia–reperfusion injury as shown by reduced levels of serum creatinine or blood urea nitrogen compared to control mice. Further studies indicated that fewer CD4-cells infiltrated the post-ischemic kidneys of IL-16-deficient mice and that the protective effect of IL-16 antibody treatment was lymphocyte-dependent. Our results suggest that IL-16 is a critical factor in the development of inflammation-mediated renal injury and may be a therapeutic target for prevention of ischemia–reperfusion injury of the kidney. T-cell-mediated renal injury is a major cause of kidney transplant rejection and renal failure; hence, understanding T-cell migration within the kidney is important for preventing renal injury. Interleukin (IL)-16 is a T-cell chemoattractant produced by leukocytes. Here we measured IL-16 expression in the kidney and its role in renal ischemia–reperfusion injury induced by different conditions in several strains of mice. IL-16 was strongly expressed in distal and proximal straight tubules of the kidney. The IL-16 precursor protein was cleaved to a chemotactic form in cultured tubular epithelial cells. Inactivation of IL-16 by antibody therapy or IL-16 deficiency prevented ischemia–reperfusion injury as shown by reduced levels of serum creatinine or blood urea nitrogen compared to control mice. Further studies indicated that fewer CD4-cells infiltrated the post-ischemic kidneys of IL-16-deficient mice and that the protective effect of IL-16 antibody treatment was lymphocyte-dependent. Our results suggest that IL-16 is a critical factor in the development of inflammation-mediated renal injury and may be a therapeutic target for prevention of ischemia–reperfusion injury of the kidney. Renal ischemia–reperfusion injury (IRI) contributes to function loss and long-term changes of kidney transplants, and also is a common cause for acute renal failure or acute kidney injury in native kidneys.1.Thadhani R. Pascual M. Bonventre J.V. Acute renal failure.N Engl J Med. 1996; 334: 1448-1460Crossref PubMed Scopus (1434) Google Scholar, 2.Cecka M. Clinical outcome of renal transplantation. Factors influencing patient and graft survival.Surg Clin North Am. 1998; 78: 133-148Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 3.Shoskes D.A. Cecka J.M. Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection.Transplantation. 1998; 66: 1697-1701Crossref PubMed Scopus (345) Google Scholar To date, the pathogenesis of renal IRI is not fully understood, but leukocyte infiltration, particularly T cells, is currently considered as a crucial pathogenic factor for renal tubular epithelial cell (TEC) and endothelial cell death (apoptosis and necrosis).4.Friedewald J.J. Rabb H. Inflammatory cells in ischemic acute renal failure.Kidney Int. 2004; 66: 486-491Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar, 5.Molitoris B.A. Sutton T.A. Endothelial injury and dysfunction: role in the extension phase of acute renal failure.Kidney Int. 2004; 66: 496-499Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 6.Ysebaert D.K. De Greef K.E. De Beuf A. et al.T cells as mediators in renal ischemia/reperfusion injury.Kidney Int. 2004; 66: 491-496Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar Indeed, T-cell deficiency results in resistance to renal IRI, which could be restored by the adoptive transfer of naive T cells in an animal model.7.Burne-Taney M.J. Yokota-Ikeda N. Rabb H. Effects of combined T- and B-cell deficiency on murine ischemia reperfusion injury.Am J Transplant. 2005; 5: 1186-1193Crossref PubMed Scopus (82) Google Scholar Targeting T cells, such as blocking T-cell costimulating pathway CD28-B7, has been found to be effective in the prevention of renal IRI.8.Chandraker A. Takada M. Nadeau K.C. et al.CD28-b7 blockade in organ dysfunction secondary to cold ischemia/reperfusion injury.Kidney Int. 1997; 52: 1678-1684Abstract Full Text PDF PubMed Scopus (89) Google Scholar, 9.Takada M. Chandraker A. Nadeau K.C. et al.The role of the B7 costimulatory pathway in experimental cold ischemia/reperfusion injury.J Clin Invest. 1997; 100: 1199-1203Crossref PubMed Scopus (194) Google Scholar, 10.De Greef K.E. Ysebaert D.K. Dauwe S. et al.Anti-B7-1 blocks mononuclear cell adherence in vasa recta after ischemia.Kidney Int. 2001; 60: 1415-1427Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Therefore, understanding of the molecular mechanisms by which T cells are recruited and migrate to the post-ischemic renal tissue is critical for the development of new therapeutic strategy for patients with acute kidney injury and kidney transplant rejection. Interleukin (IL)-16 was first identified as a CD8+ lymphocyte-producing T-cell chemoattractant factor.11.Center D.M. Cruikshank W. Modulation of lymphocyte migration by human lymphokines. I. Identification and characterization of chemoattractant activity for lymphocytes from mitogen-stimulated mononuclear cells.J Immunol. 1982; 128: 2563-2568PubMed Google Scholar, 12.Cruikshank W. Center D.M. Modulation of lymphocyte migration by human lymphokines. II. Purification of a lymphotactic factor (LCF).J Immunol. 1982; 128: 2569-2574PubMed Google Scholar, 13.Laberge S. Cruikshank W.W. Kornfeld H. Center D.M. Histamine-induced secretion of lymphocyte chemoattractant factor from CD8+ T cells is independent of transcription and translation. Evidence for constitutive protein synthesis and storage.J Immunol. 1995; 155: 2902-2910PubMed Google Scholar So far it has been found in a variety of leukocytes and in some non-immune cells (that is, fibroblasts, lung epithelial cells, and brain cells).14.Chupp G.L. Wright E.A. Wu D. et al.Tissue and T cell distribution of precursor and mature IL-16.J Immunol. 1998; 161: 3114-3119PubMed Google Scholar,15.Cruikshank W.W. Kornfeld H. Center D.M. Interleukin-16.J Leukoc Biol. 2000; 67: 757-766PubMed Google Scholar The secreted mature form of IL-16 is released from pre-formed IL-16 protein (pro-IL-16) by cleavage of caspase-3.16.Baier M. Bannert N. Werner A. et al.Molecular cloning, sequence, expression, and processing of the interleukin 16 precursor.Proc Natl Acad Sci USA. 1997; 94: 5273-5277Crossref PubMed Scopus (121) Google Scholar,17.Zhang Y. Center D.M. Wu D.M. et al.Processing and activation of pro-interleukin-16 by caspase-3.J Biol Chem. 1998; 273: 1144-1149Crossref PubMed Scopus (192) Google Scholar Although the biological functions of IL-16 are not completely known, its chemotactic activity seems the most prominent, and more importantly it does not require earlier activation of target cells (for example, T cell and monocyte)18.Cruikshank W.W. Berman J.S. Theodore A.C. et al.Lymphokine activation of T4+ T lymphocytes and monocytes.J Immunol. 1987; 138: 3817-3823PubMed Google Scholar, 19.Cruikshank W.W. Greenstein J.L. Theodore A.C. Center D.M. Lymphocyte chemoattractant factor induces CD4-dependent intracytoplasmic signaling in lymphocytes.J Immunol. 1991; 146: 2928-2934PubMed Google Scholar, 20.Cruikshank W.W. Center D.M. Nisar N. et al.Molecular and functional analysis of a lymphocyte chemoattractant factor: association of biologic function with CD4 expression.Proc Natl Acad Sci USA. 1994; 91: 5109-5113Crossref PubMed Scopus (223) Google Scholar, 21.Cruikshank W. Kornfeld H. Berman J. et al.Biological activity of interleukin-16.Nature. 1996; 382: 501-502Crossref PubMed Scopus (10) Google Scholar or connective tissue matrices.11.Center D.M. Cruikshank W. Modulation of lymphocyte migration by human lymphokines. I. Identification and characterization of chemoattractant activity for lymphocytes from mitogen-stimulated mononuclear cells.J Immunol. 1982; 128: 2563-2568PubMed Google Scholar Thus, IL-16 may act as an initial chemokine for recruitment of leukocytes in the development of local inflammation. Indeed, a recent study indicates that in the animal model of peripheral ischemia, the contribution of CD8+ infiltrate to the early phase of collateral developments depends on its IL-16 production, which recruits CD4+ mononuclear cells.22.Stabile E. Kinnaird T. la Sala A. et al.CD8+ T lymphocytes regulate the arteriogenic response to ischemia by infiltrating the site of collateral vessel development and recruiting CD4+ mononuclear cells through the expression of interleukin-16.Circulation. 2006; 113: 118-124Crossref PubMed Scopus (117) Google Scholar In this study, we have examined the expression of IL-16 in the nephron and TEC cultures. Our results demonstrate that constitutive expression of pro-IL-16 is strongly detected in various segments of the nephron, including distal tubules, glomerula, and proximal straight tubules in the medulla and chemotactic form of IL-16 in TEC cultures. Neutralization of IL-16 by monoclonal antibody treatment results in the reduction of renal IRI in a murine model. The presence of IL-16 (mRNA and protein) was first examined by reverse transcription-PCR and western blot. As shown in Figure 1a, IL-16 mRNA was detected in RNA samples from primary and cloned NG1.1 TECs as well as naive kidney sections. The expression of IL-16 in the kidney and TEC cultures was further confirmed by the presence of its protein, indicated in western blot. As demonstrated in Figure 1b, there was a prominent anti-IL-16 antibody-bound protein in the protein extracts of TEC and kidney tissue, which likely was pro-IL-16 protein. The specificity of this antibody in the detection of IL-16 protein was confirmed by western blot using protein extract from IL-16-deficient kidneys, in which no pro-IL-16 protein was shown (Figure 1c). Furthermore, it was noted that the position of pro-IL-16 protein in TEC was different from that in kidney tissue in the blot, indicating that the modification occurred to this protein when the kidney cells were grown in a culture system in vitro. In agreement with that, a small size of protein (∼19 kDa) was uniquely recognized by anti-IL-16 antibody in the protein extracts of TEC cultures, indicating the presence of a mature form of IL-16 from these TEC cultures, respectively. To further evaluate whether the mature form of IL-16 in TEC culture had chemotactic activity, the leukocyte chemotaxis to protein extracts of TEC (primary and NG1.1 cells) vs naive kidney tissue was examined by chemotaxis assay. As shown in Figure 2, protein extracts from both primary and cloned NG1.1 TECs had a significant chemotactic activity of IL-16 to syngeneic splenocytes. In control IgG-treated cell extracts, the maximal migration was seen in a range of 0.1–10 μg ml−1 of protein extract, in which 39.6±3.2% of migration was stimulated by 1 μg of protein extract of NG1.1 TEC or 42.9±3.1% by 1 μg of protein extract of primary TEC, whereas there was no chemotactic activity in the extracts of naive kidney tissue (data not shown). The chemotactic activity in these TEC extracts was significantly eliminated by the presence of anti-IL-16 monoclonal antibody, indicating the presence of chemotactic IL-16 in TEC cultures, but not in naive kidney. Renal expression of pro-IL-16 protein in naive kidney was examined using immunohistochemical staining. All control staining including IL-16-deficient kidney tissue was negative (Figure 3a). The positive staining of pro-IL-16 was found in whole naive kidney (cortex, outer and inner medulla), but different segments of nephron had various levels of pro-IL-16 protein (Figure 3a). In the cortex region, the staining was largely in contrast among different structures, in which the strongest staining of pro-IL-16 was localized in distal convoluted tubules, whereas the staining of this protein was relatively faint in proximal convoluted tubules as well as in the glomerula (Figure 3b and c). Staining in the medulla, however, was moderate as compared to those in the distal convoluted tubules, and was more or less the same among various structures (Figure 3b and d). Very interestingly, pro-IL-16 staining was different in proximal tubules in different locations. As shown in Figure 3d, the levels of staining in the proximal straight tubules in the outer medulla were higher than those in the proximal convoluted tubules in the cortex, whereas no remarkable difference was seen between distal convoluted and straight tubules in these two locations. Renal IRI could be induced in the uni-nephrectomized B6 male mice. First, we tested whether kidney injury resulted in the release of IL-16. Levels of IL-16 protein in urine samples were measured using enzyme-linked immunosorbent assay and were collected after 24 or 48 h post-ischemia–reperfusion. As shown in Figure 4a, a significant amount of IL-16 protein was detected in the urine from mice with renal IRI. In the urine from normal naive mice, no detectable amount of IL-16 was seen. In contrast, in mice with ischemic kidneys, IL-16 protein could reach to 2.58±1.37 or 1.43±0.75 ng ml−1 in the urine after 24 or 48 h post-renal IRI. However, because urine samples were not suitable for chemotaxis assay, whether urinary IL-16 had chemotactic activity was not known. To further confirm the release of IL-16 from the kidneys after renal IRI, the immunohistochemical staining of IL-16 was performed in these kidneys. As shown in Figure 4b, histological analysis with periodic acid-Schiff staining showed the levels of renal IRI in the kidney, in which less staining of IL-16 protein prevailed in all the damaged tubules (necrosis or apoptosis) as compared to those in the intact tubules. All these results suggest that it is possible that renal injury may lead to the release of renal IL-16, which may act as a chemoattractant. To understand the pathogenic role of IL-16 in inflammation-mediated kidney injury, the protective effects of anti-IL-16 monoclonal antibody therapy on kidney functions and injury were examined in a B6 mouse model of renal IRI. After 48 h of reperfusion, sera were harvested, and serum creatinine and blood urea nitrogen (BUN) were measured. As shown in Figure 5, the function of kidneys was better maintained by anti-IL-16 antibody therapy, indicated by lower levels of serum creatinine and BUN in the mice treated with anti-IL-16 antibody (clone 14.1, 100 μg per mouse). Serum creatinine levels in anti-IL-16 IgG-treated mice were 37.0±7.1 μM, which were significantly lower than 93.0±15.4 μM in the control IgG group (P=0.0015) (Figure 5a). The sham-operated control was 24.0±2.5 μM. The beneficial effect of neutralization of IL-16 on renal function was further supported by similar data in the measurement of BUN in the same groups of mice (18.0±4.2 mM in the anti-IL-16 IgG group vs 35.0±7.4 mM in the control IgG group, P=0.0279) (Figure 5b). These data were further confirmed using IL-16 knockout (KO) mice. As shown in Figure 6, deficiency in IL-16 expression in mice resulted in resistance to IRI, indicated by lower levels of serum creatinine and BUN in KO mice as compared to those in wild-type (WT) mice. Serum creatinine levels in KO mice were 49.6±8.3 μM, which were significantly lower than 148±15.4 μM in the WT group (P=0.0024) (Figure 6a). Similar data in the measurement of BUN were seen in these mice (22.4±3.7 mM in the KO group vs 61±7.6 mM in the WT group, P=0.0002) (Figure 6b).Figure 6Resistance to renal IRI in IL-16 knockout (KO) mice. Both Balb/c (WT) and IL-16 KO (Balb/c background) mice were subjected to renal ischemia-reperfusion at 34 °C of body temperature for 60 min. Sera were collected after 48 h of reperfusion. Kidney function was determined by measurement of serum creatinine and urea (BUN). (a) Serum creatinine levels. Data are presented as mean±s.e.m. of 12 mice in the WT control group or of nine mice in the KO group. P=0.0024 (KO vs WT). (b) BUN levels. BUN was measured in the same sera. Data are presented as mean±s.e.m. P=0.0002 (KO vs WT).View Large Image Figure ViewerDownload (PPT) The protection of renal function by anti-IL-16 antibody therapy was further confirmed by the reduction of renal tubular injury in these mice. As shown in Figure 7, less renal injury was found in the kidneys of the mice that received anti-IL-16 therapy compared to control kidneys, indicated by 22.7±2.8% of tubular necrosis/vacuolization in the anti-IL-16 antibody-treated group as compared to 38.7±3.8% in the control group (P=0.0033). The basal levels of tubular necrosis in sham-operated mice were 3.8±3.8%. Taken together, these results indicate a critical role of IL-16, possibly released from ischemic renal tissue, in the pathogenesis of renal IRI. IL-16, a ligand for CD4 antigen, has been well characterized as an important chemokine for T-cell migration. To evaluate whether its chemotactic activity was a part of the mechanism by which T cells (particularly CD4+ T cells) migrated to ischemic kidney leading to renal injury, we first examined the impact of IL-16 deficiency on migration of CD4+ cells to post-ischemic kidneys. After 24 h of IRI, the total infiltrates in ischemic kidneys of IL-16 KO mice were not significantly different from those in WT mice (data not shown). However, the percentage of CD4+ infiltrates in ischemic kidneys of IL-16 KO mice (1.28±0.3%) was less than those in WT mice (4.73±2.1%; P=0.0082) (Figure 8). Second, we tested the effect of anti-IL-16 antibody therapy on renal IRI in lymphocyte-deficient mice. As shown in Table 1, NOD-scid/scid mice (SCID) had a large deficiency in the number of lymphocytes as compared to those in B6 mice. The most notable deficiency in lymphocytes of SCID mice was CD4+ T cells, which was only equal to 3% of the same phenotype in B6 mice and was demonstrated to be a major pathogenic mediator in renal IRI.23.Burne M.J. Daniels F. El Ghandour A. et al.Identification of the CD4+ T cell as a major pathogenic factor in ischemic acute renal failure.J Clin Invest. 2001; 108: 1283-1290Crossref PubMed Scopus (366) Google Scholar,24.Yokota N. Daniels F. Crosson J. Rabb H. Protective effect of T cell depletion in murine renal ischemia–reperfusion injury.Transplantation. 2002; 74: 759-763Crossref PubMed Scopus (116) Google Scholar If the pathogenic role of IL-16 in renal IRI was dependent on its chemotactic activity on lymphocytes, particularly CD4+ T cell, the protective effects of anti-IL-16 antibody therapy on renal IRI would be reduced in SCID mice as compared to the results in B6 mice (Figure 5). Expectedly, induction of renal IRI in SCID mice mainly depends on non-lymphocyte factors, whereas in B6 mice, both T cells or lymphocytes and non-lymphocyte factors contribute to renal IRI. The antibody treatment and the number of animals were the same in these two studies for comparison. As shown in Figure 9, the reduction of renal IRI by anti-IL-16 antibody in SCID mice was not as effective as seen in B6 mice. The levels of serum creatinine in anti-IL-16 antibody-treated mice were 43±10 μM, which were not statistically different from 72±23.5 μM in the control IgG-treated group (P=0.1405). In line with that, the levels of BUN between these two groups of mice were also not significantly different (22±4.8 vs 33±9.1 mM, P=0.1331). Our data may imply that the pathogenic role of IL-16 may depend on lymphocytes, suggesting that the chemotactic activity of this cytokine to lymphocyte effectors contributes to the pathogenesis of renal IRI.Table 1Lymphocyte deficiency in SCID miceC57BL/6J (B6)SCIDProportion (%)aThe proportion of lymphocytes in SCID mice was calculated as a percentage of lymphocytes in B6 mice.Total splenocytes/ mouse ( × 106)98.1±11.514.7±1.215CD4 T cells (%)16.6±3.03.5±0.63CD8 T cells (%)9.0±2.64.8±2.38B cells (%)54.9±0.028.1±4.97.7FACS, fluorescence-activated cell sorting; SCID, NOD-scid/scid.The phenotype of lymphocytes was identified and counted by FACS analysis. CD4 T cell, CD4+TCR+ cell; CD8 T cell, CD8+TCR+; B cell, B220+ cells. Data were presented as mean±s.d. (n=4).a The proportion of lymphocytes in SCID mice was calculated as a percentage of lymphocytes in B6 mice. Open table in a new tab Figure 9Less effectiveness of anti-IL-16 antibody therapy in lymphocyte-deficient NOD-scid/scid mice. NOD-scid/scid male mice were subjected to renal ischemia–reperfusion at 40 °C of body temperature for 60 min and received either anti-IL-16 IgG or control IgG (in 200 μl of saline) through inferior vena cava (IVC) injection. Sera were collected after 48 h of reperfusion. Kidney function was determined by measurement of serum creatinine and urea (BUN). (a) Serum creatinine levels. Data are presented as mean±s.e.m. of 11 mice in each group. P=0.1405 (anti-IL-16 IgG vs control IgG). (b) BUN level. BUN was measured in the same sera. Data are presented as mean±s.e.m. P=0.1331 (anti-IL-16 IgG vs control IgG).View Large Image Figure ViewerDownload (PPT) FACS, fluorescence-activated cell sorting; SCID, NOD-scid/scid. The phenotype of lymphocytes was identified and counted by FACS analysis. CD4 T cell, CD4+TCR+ cell; CD8 T cell, CD8+TCR+; B cell, B220+ cells. Data were presented as mean±s.d. (n=4). CD4+ T cells, particularly the helper T cells (Th1) subset, are important mediators for renal IRI.23.Burne M.J. Daniels F. El Ghandour A. et al.Identification of the CD4+ T cell as a major pathogenic factor in ischemic acute renal failure.J Clin Invest. 2001; 108: 1283-1290Crossref PubMed Scopus (366) Google Scholar, 24.Yokota N. Daniels F. Crosson J. Rabb H. Protective effect of T cell depletion in murine renal ischemia–reperfusion injury.Transplantation. 2002; 74: 759-763Crossref PubMed Scopus (116) Google Scholar, 25.Day Y.J. Huang L. Ye H. et al.Renal ischemia–reperfusion injury and adenosine 2A receptor-mediated tissue protection: the role of CD4+ T cells and IFN-gamma.J Immunol. 2006; 176: 3108-3114Crossref PubMed Scopus (171) Google Scholar, 26.Marques V.P. Goncalves G.M. Feitoza C.Q. et al.Influence of TH1/TH2 switched immune response on renal ischemia–reperfusion injury.Nephron Exp Nephrol. 2006; 104: E48-E56Crossref PubMed Scopus (46) Google Scholar However, the mechanisms by which these cells are directed to migrate into post-ischemic kidneys or nephrons remain largely unknown. Our results for the first time show the presence of IL-16, a major T-cell chemoattractant factor15.Cruikshank W.W. Kornfeld H. Center D.M. Interleukin-16.J Leukoc Biol. 2000; 67: 757-766PubMed Google Scholar in kidney tissue. Under the stress of in vitro culture, the pro-IL-16 in TEC can be cleaved to a chemotactic mature form of IL-16. Release of IL-16 protein to urine is detected in mice with ischemic kidneys, and neutralization of IL-16 with monoclonal antibody has a beneficial effect on the reduction of renal IRI, which is lymphocyte-dependent. To date, IL-16 has been mainly found in leukocytes including CD4+ and CD8+ T cells,15.Cruikshank W.W. Kornfeld H. Center D.M. Interleukin-16.J Leukoc Biol. 2000; 67: 757-766PubMed Google Scholar in which pro-IL-16 is cleaved by caspase-3 into two active molecules, secreted COOH-terminal peptide as mature IL-1617.Zhang Y. Center D.M. Wu D.M. et al.Processing and activation of pro-interleukin-16 by caspase-3.J Biol Chem. 1998; 273: 1144-1149Crossref PubMed Scopus (192) Google Scholar and nuclear-translocated NH2-terminal peptide.27.Wilson K.C. Cruikshank W.W. Center D.M. Zhang Y. Prointerleukin-16 contains a functional CcN motif that regulates nuclear localization.Biochemistry. 2002; 41: 14306-14312Crossref PubMed Scopus (23) Google Scholar However, the regulations of IL-16 transcription (mRNA), translation (pro-IL-16 protein), and post-translational modification (caspase-3 cleavage) are different in various types of cells. For example, IL-16 mRNA constitutively expresses in both CD4+ and CD8+ T cells, but mature IL-16 is spontaneously secreted from CD8+ T cells,13.Laberge S. Cruikshank W.W. Kornfeld H. Center D.M. Histamine-induced secretion of lymphocyte chemoattractant factor from CD8+ T cells is independent of transcription and translation. Evidence for constitutive protein synthesis and storage.J Immunol. 1995; 155: 2902-2910PubMed Google Scholar whereas CD4+ T cells only secrete IL-16 upon stimulation with antigen or mitogen.28.Wu D.M. Zhang Y. Parada N.A. et al.Processing and release of IL-16 from CD4+ but not CD8+ T cells is activation dependent.J Immunol. 1999; 162: 1287-1293PubMed Google Scholar Similar to CD4+ T cells, we demonstrate that TEC constitutively express IL-16 mRNA and pro-IL-16 protein (Figures 1 and 3), which can be cleaved to chemotactic IL-16 upon exposure to in vitro environments (Figure 2), suggesting that renal IL-16 may act as an initial chemokine for leukocyte migration to stressed nephrons. In addition, it is unknown whether caspase-3 cleaves pro-IL-16 to release its chemotactic form in TEC, but western blot indicated a slower mobility of pro-IL-16 protein from TEC cultures during the electrophoresis in sodium dodecyl sulfate-polyacrylamide gel electrophoresis as compared to that from naive kidney tissue (Figure 1b), suggesting that removal of chemotactic peptide (IL-16) from pro-IL-16 protein may lose the hydrophobic residues and results in reduction of electronic charges on the pro-IL-16 protein. In renal IRI, a prominent pathological feature is tubular injury, including both acute necrotic and apoptotic cell death,29.Padanilam B.J. Cell death induced by acute renal injury: a perspective on the contributions of apoptosis and necrosis.Am J Physiol Renal Physiol. 2003; 284: F608-F627Crossref PubMed Scopus (300) Google Scholar which are induced by infiltrating leukocytes including T cells as well as activation of complements.30.Rabb H. O'Meara Y.M. Maderna P. et al.Leukocytes, cell adhesion molecules and ischemic acute renal failure.Kidney Int. 1997; 51: 1463-1468Abstract Full Text PDF PubMed Scopus (254) Google Scholar, 31.Rabb H. Daniels F. O'Donnell M. et al.Pathophysiological role of T lymphocytes in renal ischemia–reperfusion injury in mice.Am J Physiol Renal Physiol. 2000; 279: F525-F531PubMed Google Scholar, 32.Zhou W. Farrar C.A. Abe K. et al.Predominant role for C5b-9 in renal ischemia/reperfusion injury.J Clin Invest. 2000; 105: 1363-1371Crossref PubMed Scopus (362) Google Scholar, 33.de Vries B. Kohl J. Leclercq W.K. et al.Complement factor C5a mediates renal ischemia–reperfusion injury independent from neutrophils.J Immunol. 2003; 170: 3883-3889Crossref PubMed Scopus (186) Google Scholar Indeed, in the mouse model, mice lacking T lymphocytes are protected from renal IRI,31.Rabb H. Daniels F. O'Donnell M. et al.Pathophysiological role of T lymphocytes in renal ischemia–reperfusion injury in mice.Am J Physiol Renal Physiol. 2000; 279: F525-F531PubMed Google Scholar and the injury can be restored after the adoptive transfer of naive T cells.7.Burne-Taney M.J. Yokota-Ikeda N. Rabb H. Effects of combined T- and B-cell deficiency on murine ischemia reperfusion injury.Am J Transplant. 2005; 5: 1186-1193Crossref PubMed Scopus (82) Google Scholar Furthermore, numerous studies indicate that CD4+ T cells, particularly interferon-γ-producing Th1 phenotype, play a crucial role in renal IRI.6.Ysebaert D.K. De Greef K.E. De Beuf A. et al.T cells as mediators in renal ischemia/reperfusion injury.Kidney Int. 2004; 66: 491-496Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 7.Burne-Taney M.J. Yokota-Ikeda N. Rabb H. Effects of combined T- and B-cell deficiency on murine ischemia reperfusion injury.Am J Transplant. 2005; 5: 1186-1193Crossref PubMed Scopus (82) Google Scholar, 23.Burne M.J. Daniels F. El Ghandour A. et al.Identification of the CD4+ T cell as a major pathogenic factor in ischemic acute renal failure.J Clin Invest. 2001; 108: 1283-1290Crossref PubMed Scopus (366) Google Scholar, 24.Yokota N. Daniels F. Crosson J. Rabb H. Protective effect of T cell depletion in murine renal ischemia–reperfusion injury.Transplantation. 2002; 74: 759-763Crossref PubMed Scopus (116) Google Scholar, 26.Marques V.P. Goncalves G.M. Feitoza C.Q. et al.Influence of TH1/TH2 switched immune response on renal ischemia–reperfusion injury.Nephron Exp Nephrol. 2006; 104: E48-E56Crossref PubMed Scopus (46) Google Scholar, 34.Yokota N. Burne-Taney M. Racusen L. Rabb H. Contrasting roles for STAT4 and STAT6 signal transduction pathways in murine renal ischemia–reperfusion injury.Am J Physiol Renal Physiol. 2003; 285: F319-F325Crossref PubMed Scopus (21) Google Scholar However, the molecular mechanisms underlying the migration of CD4+ effector T cells to ischemic kidney to damage the nephron are not fully understood. It has been shown that renal vascular endothelial cells are stimulated by ischemia/reperfusion to express adhesion molecules, such as intercellular adhesion molecule-1,35.Kelly K.J. Williams Jr, W.W. Colvin R.B. et al.Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury.J Clin Invest. 1996; 97: 1056-1063Crossref PubMed Scopus (637) Google Scholar,36.Rabb H. Mendiola C.C. Saba S.R. et al.Antibodies to ICAM-1 protect kidneys in severe ischemic reperfusion inju" @default.
• W2028628211 created "2016-06-24" @default.
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• W2028628211 date "2008-02-01" @default.
• W2028628211 modified "2023-10-16" @default.
• W2028628211 title "Decreased renal ischemia–reperfusion injury by IL-16 inactivation" @default.
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