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• W2007681310 abstract "Mechanism of steroid action in renal epithelial cells. Renal tubular epithelial cells (TEC) are thought to play an active role in tubulointerstitial inflammation. Various immune and non-immune factors activate TEC to produce a variety of cytokines and chemokines, contributing to attraction of inflammatory cells to the kidney. The proinflammatory transcription factor nuclear factor-κB (NF-κB) appears to be a key player in these responses and tubular expression of NF-κB has been demonstrated in vitro and in vivo. Although glucocorticoids are known to inhibit NF-κB activation at different levels, the proinflammatory capacity of TEC was not inhibited. In contrast, glucocorticoids seemed to enhance the profibrotic response of TEC, emphasizing the cell-type specific characteristics of glucocorticoid action. We propose that specific inhibition of NF-κB activation in TEC might be an attractive strategy for therapeutic intervention in renal inflammation. Mechanism of steroid action in renal epithelial cells. Renal tubular epithelial cells (TEC) are thought to play an active role in tubulointerstitial inflammation. Various immune and non-immune factors activate TEC to produce a variety of cytokines and chemokines, contributing to attraction of inflammatory cells to the kidney. The proinflammatory transcription factor nuclear factor-κB (NF-κB) appears to be a key player in these responses and tubular expression of NF-κB has been demonstrated in vitro and in vivo. Although glucocorticoids are known to inhibit NF-κB activation at different levels, the proinflammatory capacity of TEC was not inhibited. In contrast, glucocorticoids seemed to enhance the profibrotic response of TEC, emphasizing the cell-type specific characteristics of glucocorticoid action. We propose that specific inhibition of NF-κB activation in TEC might be an attractive strategy for therapeutic intervention in renal inflammation. Influx of monocytes and T cells into the tubulointerstitial area of the kidney is a hallmark of many renal inflammatory diseases. Renal tubular epithelial cells (TEC) are an important source of cytokines and chemokines and may thereby play an important role in the attraction of these cells to the kidney [1.van Kooten C. Daha M.R. van Es L.A. Tubular epithelial cells: A critical cell type in the regulation of renal inflammatory processes.Exp Nephrol. 1999; 7: 429-437Crossref PubMed Scopus (64) Google Scholar]. Glucocorticoids are potent suppressors of the immune system and are therefore used as therapeutic treatment in a broad range of autoimmune and inflammatory diseases. One of the major anti-inflammatory actions of glucocorticoids is suppression of cytokine production [2.Almawi W.Y. Hess D.A. Rieder M.J. Multiplicity of glucocorticoid action in inhibiting allograft rejection.Cell Transplant. 1998; 7: 511-523Crossref PubMed Scopus (32) Google Scholar]. Nuclear factor-κB (NF-κB) is a proinflammatory transcription factor that regulates the expression of many inflammatory mediators [3.Li Q. Verma I.M. NF-kappaB regulation in the immune system.Nat Rev Immunol. 2002; 2: 725-734Crossref PubMed Scopus (2983) Google Scholar]. As a key regulator of immune responses, NF-κB has been suggested to play a pivotal role in a variety of immune-mediated pathophysiologic conditions, including renal disease [4.Guijarro C. Egido J. Transcription factor-kappa B (NF-kappa B) and renal disease.Kidney Int. 2001; 59: 415-424Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar]. Inhibition of cytokine production by glucocorticoids has been attributed to inhibition of NF-κB [5.Lee J.I. Burckart G.J. Nuclear factor kappa B: Important transcription factor and therapeutic target.J Clin Pharmacol. 1998; 38: 981-993Crossref PubMed Scopus (300) Google Scholar, 6.McKay L.I. Cidlowski J.A. Molecular control of immune/inflammatory responses: Interactions between nuclear factor-kappa B and steroid receptor-signaling pathways.Endocr Rev. 1999; 20: 435-459Crossref PubMed Google Scholar]. In recent years, the function of glucocorticoids has been investigated in a variety of cell types [7.Auwardt R.B. Mudge S.J. Chen C.G. Power D.A. Regulation of nuclear factor kappaB by corticosteroids in rat mesangial cells.J Am Soc Nephrol. 1998; 9: 1620-1628PubMed Google Scholar, 8.Miyazawa K. Mori A. Okudaira H. Regulation of interleukin-1beta-induced interleukin-6 gene expression in human fibroblast-like synoviocytes by glucocorticoids.J Biochem. 1998; 124 (Tokyo): 1130-1137Crossref PubMed Scopus (26) Google Scholar, 9.John M. Hirst S.J. Jose P.J. et al.Human airway smooth muscle cells express and release RANTES in response to T helper 1 cytokines: regulation by T helper 2 cytokines and corticosteroids.J Immunol. 1997; 158: 1841-1847PubMed Google Scholar]. Furthermore, the interaction between glucocorticoids and NF-κB has been subject of numerous studies [10.Scheinman R.I. Cogswell P.C. Lofquist A.K. Baldwin A.S.J. Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids.Science. 1995; 270: 283-286Crossref PubMed Scopus (1522) Google Scholar, 11.Auphan N. DiDonato J.A. Rosette C. et al.Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis.Science. 1995; 270: 286-290Crossref PubMed Scopus (2031) Google Scholar, 12.Ray A. Prefontaine K.E. Physical association and functional antagonism between the p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor.Proc Natl Acad Sci USA. 1994; 91: 752-756Crossref PubMed Scopus (863) Google Scholar, 13.Caldenhoven E. Liden J. Wissink S. et al.Negative cross-talk between RelA and the glucocorticoid receptor: A possible mechanism for the antiinflammatory action of glucocorticoids.Mol Endocrinol. 1995; 9: 401-412Crossref PubMed Google Scholar, 14.Sheppard K.A. Phelps K.M. Williams A.J. et al.Nuclear integration of glucocorticoid receptor and nuclear factor-kappaB signaling by CREB-binding protein and steroid receptor coactivator-1.J Biol Chem. 1998; 273: 29291-29294Crossref PubMed Scopus (258) Google Scholar, 15.De Bosscher K. Vanden Berghe W. Vermeulen L. et al.Glucocorticoids repress NF-kappaB-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell.Proc Natl Acad Sci USA. 2000; 97: 3919-3924Crossref PubMed Scopus (260) Google Scholar, 16.Nissen R.M. Yamamoto K.R. The glucocorticoid receptor inhibits NFkappaB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain.Genes Dev. 2000; 14: 2314-2329Crossref PubMed Scopus (442) Google Scholar]. One important lesson to learn from these studies is that the effect of glucocorticoids is cell type–specific and that one should be careful to extrapolate data from one cell type to another. In the present review, we describe the mechanism of steroid action in renal tubular epithelial cells. We present an overview of the levels of interaction between steroids and NF-κB and demonstrate the importance of this interaction for regulation of cytokine production by TEC and the potential implications for renal inflammation. Progressive loss of renal function is thought to be the result of a common pathogenic pathway independent of the original disease. This progressive chronic renal failure is associated with interstitial infiltration and tubular injury [17.Remuzzi G. Ruggenenti P. Benigni A. Understanding the nature of renal disease progression.Kidney Int. 1997; 51: 2-15Abstract Full Text PDF PubMed Scopus (578) Google Scholar, 18.Becker G.J. Hewitson T.D. The role of tubulointerstitial injury in chronic renal failure.Curr Opin Nephrol Hypertens. 2000; 9: 133-138Crossref PubMed Scopus (130) Google Scholar]. Similar processes are observed in renal allograft rejection, in which tubulointerstitial infiltration of mainly T cells and monocytes is a prominent feature [19.Suthanthiran M. Strom T.B. Renal transplantation.N Engl J Med. 1994; 331: 365-376Crossref PubMed Scopus (351) Google Scholar, 20.Robertson H. Kirby J.A. Post-transplant renal tubulitis: The recruitment, differentiation and persistence of intra-epithelial T cells.Am J Transplant. 2003; 3: 3-10Crossref PubMed Scopus (48) Google Scholar]. Infiltration is critically dependent on the expression of chemokines [21.Baggiolini M. Chemokines and leukocyte traffic.Nature. 1998; 392: 565-568Crossref PubMed Scopus (2317) Google Scholar], which are produced intrarenally [22.Segerer S. Nelson P.J. Schlondorff D. Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies.J Am Soc Nephrol. 2000; 11: 152-176PubMed Google Scholar, 23.Rovin B.H. Phan L.T. Chemotactic factors and renal inflammation.Am J Kidney Dis. 1998; 31: 1065-1084Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar]. TECs are considered to be a central cell type in renal inflammation because they are able to produce a large variety of cytokines [interleukin (IL)-6, tumor necrosis factor-α (TNF-α)] and chemokines [IL-8/CXCL8, monocyte chemoattractant protein-1 (MCP-1)/CCL2, regulated upon activation, normal T cell expressed and secreted (RANTES)/CCL5] [1.van Kooten C. Daha M.R. van Es L.A. Tubular epithelial cells: A critical cell type in the regulation of renal inflammatory processes.Exp Nephrol. 1999; 7: 429-437Crossref PubMed Scopus (64) Google Scholar]. These chemokines are sequestered in the tubular basement membrane, providing a chemokine concentration gradient that peaks at the tubuli [20.Robertson H. Kirby J.A. Post-transplant renal tubulitis: The recruitment, differentiation and persistence of intra-epithelial T cells.Am J Transplant. 2003; 3: 3-10Crossref PubMed Scopus (48) Google Scholar]. Different circumstances might trigger TEC activation, including ischaemia/hypoxia caused by glomerular injury or transplantation procedures [18.Becker G.J. Hewitson T.D. The role of tubulointerstitial injury in chronic renal failure.Curr Opin Nephrol Hypertens. 2000; 9: 133-138Crossref PubMed Scopus (130) Google Scholar]. Another factor contributing to activation of tubular epithelial cells is exposure to protein overload due to enhanced glomerular permeability. In vitro exposure of renal epithelial cells to albumin resulted in increased production of IL-8, MCP-1, and RANTES [24.Wang Y. Rangan G.K. Tay Y.C. Harris D.C. Induction of monocyte chemoattractant protein-1 by albumin is mediated by nuclear factor kappaB in proximal tubule cells.J Am Soc Nephrol. 1999; 10: 1204-1213PubMed Google Scholar, 25.Zoja C. Donadelli R. Colleoni S. et al.Protein overload stimulates RANTES production by proximal tubular cells depending on NF-kappa B activation.Kidney Int. 1998; 53: 1608-1615Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar, 26.Tang S. Leung J.C. Abe K. et al.Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells in vitro and in vivo.J Clin Invest. 2003; 111: 515-527Crossref PubMed Scopus (209) Google Scholar]. IL-8 was predominantly secreted at the basolateral site, suggesting accumulation in the interstitial space [26.Tang S. Leung J.C. Abe K. et al.Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells in vitro and in vivo.J Clin Invest. 2003; 111: 515-527Crossref PubMed Scopus (209) Google Scholar]. Cross-talk between TECs and infiltrating leukocytes also constitutes an important part of the regulation of production of inflammatory mediators by TEC. In vitro studies have shown that TEC are strongly activated by TNF-α and IL-1, which are mainly produced by monocytes. In addition, T-cell–derived factors like IL-17 and interferon-γ (IFN-γ) and the cell surface molecule CD40L strongly induce cytokine and chemokine production by TEC [27.Kuroiwa T. Schlimgen R. Illei G.G. et al.Distinct T cell/renal tubular epithelial cell interactions define differential chemokine production: Implications for tubulointerstitial injury in chronic glomerulonephritides.J Immunol. 2000; 164: 3323-3329Crossref PubMed Scopus (75) Google Scholar, 28.Woltman A.M. De Haij S. Boonstra J.G. et al.Interleukin-17 and CD40-ligand synergistically enhance cytokine and chemokine production by renal epithelial cells.J Am Soc Nephrol. 2000; 11: 2044-2055PubMed Google Scholar, 29.Pattison J. Nelson P.J. Huie P. et al.RANTES chemokine expression in cell-mediated transplant rejection of the kidney.Lancet. 1994; 343: 209-211Abstract PubMed Scopus (230) Google Scholar, 30.van Kooten C. van der Linde X. Woltman A.M. et al.Synergistic effect of interleukin-1 and CD40L on the activation of human renal tubular epithelial cells.Kidney Int. 1999; 56: 41-51Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. The increase in chemokine production by TEC might lead to further attraction of inflammatory cells to the kidney, thereby generating an amplification loop for activation. The ratio of different chemokines produced will determine the composition of the infiltrate. Interstitial cross-talk might also be involved in T-cell proliferation at the site of inflammation. For instance, activated TEC have been shown to produce IL-15, a cytokine with T-cell growth factor activity [31.Weiler M. Kachko L. Chaimovitz C. et al.CD40 ligation enhances IL-15 production by tubular epithelial cells.J Am Soc Nephrol. 2001; 12: 80-87PubMed Google Scholar, 32.Lewis E. Weiler M. Chaimovitz C. Douvdevani A. Interleukin-15 is the main mediator of lymphocyte proliferation in cultures mixed with human kidney tubular epithelial cells.Transplantation. 2001; 72: 886-890Crossref PubMed Scopus (13) Google Scholar]. A detailed description of the various cytokines that can be produced by TEC and their respective receptors and target cells has previously been presented [33.van Kooten C. Daha M.R. Cytokine cross-talk between tubular epithelial cells and interstitial immunocompetent cells.Curr Opin Nephrol Hypertens. 2001; 10: 55-59Crossref PubMed Scopus (28) Google Scholar]. Next to chemokines, activated TEC express increased levels of adhesion molecules and major histocompatibility complex (MHC) class II, which can also be involved in the cross-talk with T cells and monocytes [34.Kirby J.A. Rajasekar M.R. Lin Y. et al.Interaction between T lymphocytes and kidney epithelial cells during renal allograft rejection.Kidney Int. 1993; 43: S124-S128Google Scholar]. TECs are not only an important source of cytokines and chemokines, but are also capable of producing profibrotic factors, including transforming growth factor beta (TGF-β) and platelet-derived growth factor (PDGF) [18.Becker G.J. Hewitson T.D. The role of tubulointerstitial injury in chronic renal failure.Curr Opin Nephrol Hypertens. 2000; 9: 133-138Crossref PubMed Scopus (130) Google Scholar, 35.Zeisberg M. Strutz F. Muller G.A. Renal fibrosis: An update.Curr Opin Nephrol Hypertens. 2001; 10: 315-320Crossref PubMed Scopus (148) Google Scholar, 36.Klahr S. Morrissey J. Progression of chronic renal disease.Am J Kidney Dis. 2003; 41: S3-S7Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar]. Furthermore, activated renal epithelial cells are able to produce endothelin-1 (ET-1), which enhances matrix synthesis by fibroblasts [17.Remuzzi G. Ruggenenti P. Benigni A. Understanding the nature of renal disease progression.Kidney Int. 1997; 51: 2-15Abstract Full Text PDF PubMed Scopus (578) Google Scholar]. Moreover, TEC might contribute directly to the excessive matrix production by synthesis of extracellular matrix components (collagens, fibronectin, laminin) [18.Becker G.J. Hewitson T.D. The role of tubulointerstitial injury in chronic renal failure.Curr Opin Nephrol Hypertens. 2000; 9: 133-138Crossref PubMed Scopus (130) Google Scholar]. Finally, it has been suggested that TEC can transdifferentiate into fibroblasts via a process called epithelial-mesenchymal transition [35.Zeisberg M. Strutz F. Muller G.A. Renal fibrosis: An update.Curr Opin Nephrol Hypertens. 2001; 10: 315-320Crossref PubMed Scopus (148) Google Scholar, 37.Iwano M. Plieth D. Danoff T.M. et al.Evidence that fibroblasts derive from epithelium during tissue fibrosis.J Clin Invest. 2002; 110: 341-350Crossref PubMed Scopus (1552) Google Scholar]. Taken together, activated tubular cells play an important role in aggravating local inflammation and fibrosis, ultimately leading to permanent loss of integrity and function of the kidney. A schematic representation of TEC activation is shown in Figure 1. Glucocorticoids are known to modulate a variety of cellular processes and play an important role in homeostasis and development. Furthermore, glucocorticoids are potent suppressors of the immune system and are therefore used as therapeutic treatment in a broad range of autoimmune and inflammatory diseases. Glucocorticoid action is mediated via binding to the glucocorticoid receptor. The inactive receptor is bound to chaperone proteins, including two heat shock protein (hsp90) subunits and is located in the cytoplasm [38.Tsai M.J. O'Malley B.W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members.Annu Rev Biochem. 1994; 63: 451-486Crossref PubMed Scopus (2586) Google Scholar, 39.Truss M. Beato M. Steroid hormone receptors: Interaction with deoxyribonucleic acid and transcription factors.Endocr Rev. 1993; 14: 459-479Crossref PubMed Scopus (588) Google Scholar]. Upon ligand binding, the activated glucocorticoid receptor dissociates from the chaperone complex and translocates to the nucleus to activate or repress transcription of glucocorticoid target genes. Stimulation of gene transcription is mediated via binding of glucocorticoid receptors to glucocorticoid responsive elements (GREs) in the promoter region of glucocorticoid-responsive genes [6.McKay L.I. Cidlowski J.A. Molecular control of immune/inflammatory responses: Interactions between nuclear factor-kappa B and steroid receptor-signaling pathways.Endocr Rev. 1999; 20: 435-459Crossref PubMed Google Scholar, 38.Tsai M.J. O'Malley B.W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members.Annu Rev Biochem. 1994; 63: 451-486Crossref PubMed Scopus (2586) Google Scholar, 39.Truss M. Beato M. Steroid hormone receptors: Interaction with deoxyribonucleic acid and transcription factors.Endocr Rev. 1993; 14: 459-479Crossref PubMed Scopus (588) Google Scholar]. One of the major anti-inflammatory actions of glucocorticoids is suppression of cytokine production [2.Almawi W.Y. Hess D.A. Rieder M.J. Multiplicity of glucocorticoid action in inhibiting allograft rejection.Cell Transplant. 1998; 7: 511-523Crossref PubMed Scopus (32) Google Scholar]. Glucocorticoids can inhibit gene transcription via negative GREs. However, several genes that are negatively regulated by steroids, including cytokine genes, do not contain a negative response element in their promoter. Expression of these genes is inhibited via glucocorticoid-induced repression of transcription factors, including activating-protein-1 (AP-1) and NF-κB [40.Cato A.C. Wade E. Molecular mechanisms of anti-inflammatory action of glucocorticoids.Bioessays. 1996; 18: 371-378Crossref PubMed Scopus (288) Google Scholar]. Many anti-inflammatory effects of glucocorticoids have been linked to their ability to inhibit the activation of NF-κB [5.Lee J.I. Burckart G.J. Nuclear factor kappa B: Important transcription factor and therapeutic target.J Clin Pharmacol. 1998; 38: 981-993Crossref PubMed Scopus (300) Google Scholar, 6.McKay L.I. Cidlowski J.A. Molecular control of immune/inflammatory responses: Interactions between nuclear factor-kappa B and steroid receptor-signaling pathways.Endocr Rev. 1999; 20: 435-459Crossref PubMed Google Scholar]. The transcription factor NF-κB is a key player of inflammatory processes regulating the expression of numerous proteins involved in inflammation [3.Li Q. Verma I.M. NF-kappaB regulation in the immune system.Nat Rev Immunol. 2002; 2: 725-734Crossref PubMed Scopus (2983) Google Scholar]. Target genes include cytokines (IL-6), chemokines (IL-8, MCP-1, and RANTES), and cell adhesion molecules [intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1)] [5.Lee J.I. Burckart G.J. Nuclear factor kappa B: Important transcription factor and therapeutic target.J Clin Pharmacol. 1998; 38: 981-993Crossref PubMed Scopus (300) Google Scholar, 41.Barnes P.J. Karin M. Nuclear factor-kappaB: A pivotal transcription factor in chronic inflammatory diseases.N Engl J Med. 1997; 336: 1066-1071Crossref PubMed Scopus (4002) Google Scholar]. The classical form of NF-κB is a heterodimer of a p50 and a p65 subunit [41.Barnes P.J. Karin M. Nuclear factor-kappaB: A pivotal transcription factor in chronic inflammatory diseases.N Engl J Med. 1997; 336: 1066-1071Crossref PubMed Scopus (4002) Google Scholar, 42.Ghosh S. May M.J. Kopp E.B. NF-kappa B and Rel proteins: Evolutionarily conserved mediators of immune responses.Annu Rev Immunol. 1998; 16: 225-260Crossref PubMed Scopus (4365) Google Scholar]. In the cytoplasm, NF-κB is kept inactive through binding to its endogenous inhibitor, IκB-α. NF-κB can be activated by a variety of stimuli, including cytokines like IL-1 and TNF-α, which induce phosphorylation and subsequent degradation of IκB-α. The released NF-κB translocates to the nucleus to activate transcription of target genes [42.Ghosh S. May M.J. Kopp E.B. NF-kappa B and Rel proteins: Evolutionarily conserved mediators of immune responses.Annu Rev Immunol. 1998; 16: 225-260Crossref PubMed Scopus (4365) Google Scholar, 43.Karin M. Ben-Neriah Y. Phosphorylation meets ubiquitination: The control of NF-[kappa]B activity.Annu Rev Immunol. 2000; 18: 621-663Crossref PubMed Scopus (3831) Google Scholar]. Considering the important role of NF-κB in the inflammatory process it is not surprising that dysregulation of NF-κB is associated with inflammatory diseases, such as rheumatoid arthritis, asthma, and inflammatory bowel disease [5.Lee J.I. Burckart G.J. Nuclear factor kappa B: Important transcription factor and therapeutic target.J Clin Pharmacol. 1998; 38: 981-993Crossref PubMed Scopus (300) Google Scholar, 41.Barnes P.J. Karin M. Nuclear factor-kappaB: A pivotal transcription factor in chronic inflammatory diseases.N Engl J Med. 1997; 336: 1066-1071Crossref PubMed Scopus (4002) Google Scholar, 44.Baldwin Jr., A.S. Series introduction: the transcription factor NF-kappaB and human disease.J Clin Invest. 2001; 107: 3-6Crossref PubMed Google Scholar]. Increased tissue expression of NF-κB can lead to enhanced production of inflammatory mediators and the recruitment of inflammatory cells, which are characteristic of these chronic inflammatory diseases. Also in the pathogenesis of allograft rejection a crucial role for NF-κB was demonstrated [5.Lee J.I. Burckart G.J. Nuclear factor kappa B: Important transcription factor and therapeutic target.J Clin Pharmacol. 1998; 38: 981-993Crossref PubMed Scopus (300) Google Scholar, 45.Finn P.W. He H. Ma C. et al.Molecular profiling of the role of the NF-kappaB family of transcription factors during alloimmunity.J Leuko Biol. 2002; 72: 1054-1062PubMed Google Scholar]. Furthermore, NF-κB has been implicated in the process of atherosclerosis. The observation that NF-κB is also a critical regulator of cell proliferation and apoptosis has important implications for the role of NF-κB in the pathogenesis of cancer [46.Barkett M. Gilmore T.D. Control of apoptosis by Rel/NF-kappaB transcription factors.Oncogene. 1999; 18: 6910-6924Crossref PubMed Scopus (1023) Google Scholar, 47.Karin M. Cao Y. Greten F.R. Li Z.W. NF-kappaB in cancer: From innocent bystander to major culprit.Nat Rev Cancer. 2002; 2: 301-310Crossref PubMed Scopus (2112) Google Scholar, 48.Bharti A.C. Aggarwal B.B. Nuclear factor-kappa B and cancer: Its role in prevention and therapy.Biochem Pharmacol. 2002; 64: 883-888Crossref PubMed Scopus (442) Google Scholar]. The importance of NF-κB in renal disease, as demonstrated in vivo in experimental models of nephritis and tubulointerstitial disorders, has been previously reviewed [4.Guijarro C. Egido J. Transcription factor-kappa B (NF-kappa B) and renal disease.Kidney Int. 2001; 59: 415-424Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar]. The mechanism of NF-κB suppression by glucocorticoids has been studied extensively. Initially, it was postulated that steroids inhibit NF-κB activation by increasing the transcription of IκB-α, the endogenous inhibitor of NF-κB [10.Scheinman R.I. Cogswell P.C. Lofquist A.K. Baldwin A.S.J. Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids.Science. 1995; 270: 283-286Crossref PubMed Scopus (1522) Google Scholar, 11.Auphan N. DiDonato J.A. Rosette C. et al.Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis.Science. 1995; 270: 286-290Crossref PubMed Scopus (2031) Google Scholar]. The newly synthesized IκB-α could sequester NF-κB in the cytoplasm or, alternatively, remove NF-κB from DNA and transport the NF-κB complexes to the cytosol via a nuclear export signal in the N-terminal domain of IκB-α, thereby terminating NF-κB–dependent transcriptional activation [49.Huang T.T. Kudo N. Yoshida M. Miyamoto S. A nuclear export signal in the N-terminal regulatory domain of IkappaBalpha controls cytoplasmic localization of inactive NF-kappaB/IkappaBalpha complexes.Proc Natl Acad Sci USA. 2000; 97: 1014-1019Crossref PubMed Scopus (300) Google Scholar, 50.Arenzana-Seisdedos F. Thompson J. Rodriguez M.S. et al.Inducible nuclear expression of newly synthesized I kappa B alpha negatively regulates DNA-binding and transcriptional activities of NF-kappa B.Mol Cell Biol. 1995; 15: 2689-2696Crossref PubMed Google Scholar]. Subsequent studies have demonstrated that the activated glucocorticoid receptor can bind to the p65 subunit of NF-κB, thus interfering in the binding of NF-κB to DNA [12.Ray A. Prefontaine K.E. Physical association and functional antagonism between the p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor.Proc Natl Acad Sci USA. 1994; 91: 752-756Crossref PubMed Scopus (863) Google Scholar, 13.Caldenhoven E. Liden J. Wissink S. et al.Negative cross-talk between RelA and the glucocorticoid receptor: A possible mechanism for the antiinflammatory action of glucocorticoids.Mol Endocrinol. 1995; 9: 401-412Crossref PubMed Google Scholar]. However, glucocorticoid-mediated suppression of NF-κB without induction of IκB-α synthesis or inhibition of DNA binding has been shown in other studies [51.Brostjan C. Anrather J. Csizmadia V. et al.Glucocorticoid-mediated repression of NFkappaB activity in endothelial cells does not involve induction of IkappaBalpha synthesis.J Biol Chem. 1996; 271: 19612-19616Crossref PubMed Scopus (189) Google Scholar, 52.Newton R. Hart L.A. Stevens D.A. et al.Effect of dexamethasone on interleukin-1beta-(IL-1beta)-induced nuclear factor-kappaB (NF-kappaB) and kappaB-dependent transcription in epithelial cells.Eur J Biochem. 1998; 254: 81-89Crossref PubMed Scopus (95) Google Scholar, 53.Wissink S. van Heerde E.C. van der Burg B. Van der Saag P.T. A dual mechanism mediates repression of NF-kappaB activity by glucocorticoids.Mol Endocrinol. 1998; 12: 355-363Crossref PubMed Google Scholar]. In other studies it has been described that corticosteroids can interfere with the transactivating potential of NF-κB without affecting DNA binding, either by competition for limited amount of cofactors like cyclic adenosine monophosphate (cAMP)-responsive element binding protein (CREB) binding protein (CBP) and steroid receptor coactivator-1 (SRC-1) or by interference with the mechanistic interaction of p65 with the basal transcription machinery [14.Sheppard K.A. Phelps K.M. Williams A.J. et al.Nuclear integration of glucocorticoid receptor and nuclear factor-kappaB signaling by CREB-binding protein and steroid receptor coactivator-1.J Biol Chem. 1998; 273: 29291-29294Crossref PubMed Scopus (258) Google Scholar, 15.De Bosscher K. Vanden Berghe W. Vermeulen L. et al.Glucocorticoids repress NF-kappaB-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell.Proc Natl Acad Sci USA. 2000; 97: 3919-3924Crossref PubMed Scopus (260) Google Scholar, 16.Nissen R.M. Yamamoto K.R. The glucocorticoid receptor inhibits NFkappaB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain.Genes Dev. 2000; 14: 2314-2329Crossref PubMed Scopus (442) Google Scholar]. Figure 2 gives an overview of the levels of interaction between steroids and NF-κB. Treatment of renal inflammatory diseases usually includes glucocorticoids. Although glucocorticoids are known to have a profound effect on cytokine production by a variety of cell types [7.Auwardt R.B. Mudge S.J. Chen C.G. Power D.A. Regulation of nuclear factor kappaB by corticosteroids in rat mesangial cells.J Am Soc Nephrol. 1998; 9: 1620-1628PubMed Google Scholar, 8.Miyazawa K. Mori A. Okudaira H. Regulation of interleukin-1beta-induced interleukin-6 gene expression in human fibroblast-like synoviocytes by glucocorticoids.J Biochem. 1998; 124 (Tokyo): 1130-1137Crossref PubMed Scopus (26) Google Scholar, 9.John M. Hirst S.J. Jose P.J. et al.Human airway smooth muscle cells express and release RANTES in response to T helper 1 cytokines: regulation by T helper 2 cytokines and corticosteroids.J Immunol. 1997; 158: 1841-1847PubMed Google Scholar], we have recently shown that production of cytokines (IL-6) and chemokines (MCP-1 and IL-8) by primary human TEC that were activated with IL-1, TNF-α, or CD40L was insensitive to the inhibitory action of dexamethasone [54.De Haij S. Woltman A.M. Bakker A.C. et al.Production of inflammatory mediat" @default.
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• W2007681310 date "2004-05-01" @default.
• W2007681310 modified "2023-10-14" @default.
• W2007681310 title "Mechanism of steroid action in renal epithelial cells" @default.
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