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Mechanisms of Disease: regulation of RANTES (CCL5) in renal disease

Nature Clinical Practice Nephrology volume 3, pages 164–170 (2007)Cite this article

Abstract

Chemokines (chemoattractant cytokines) are fundamental regulators of immune cell movement from the bloodstream into tissues. Regulating expression of chemokines might, therefore, alleviate inflammation in autoimmune diseases and transplant rejection, or augment immune responses in cancer and immunodeficiency. RANTES (regulated upon activation, normal T cell expressed and secreted [also known as CCL5]) is a model chemokine of relevance to a myriad of diseases. Regulation of RANTES expression is complex. In fibroblasts and monocytes, rel proteins alone suffice to induce transcription of RANTES. By contrast, expression of RANTES in T lymphocytes 3–5 days after activation requires the development of a molecular complex (enhancesome) including KLF13 (Krueppel-like factor 13), rel proteins p50 and p65, and scaffolding proteins. This complex recruits enzymes involved in acetylation, methylation and phosphorylation of chromatin, and ultimately in the expression of RANTES. In addition, KLF13—the lynchpin for recruitment of this molecular complex—is itself translationally regulated. Such complex regulation of biological systems has major implications for the rational design of drugs aimed at increasing or decreasing inflammatory responses in patients.

Key Points

  • Manipulating expression of chemokines—key regulators of immune cell movement—such as RANTES (CCL5) might prove beneficial for a range of renal diseases such as acute renal failure, nephritis, nephropathy of various etiologies, and transplant rejection

  • Key regulators of RANTES (CCL5) expression include rel proteins (in fibroblasts and monocytes), and an 'enhancesome complex' comprising KLF13 (Krueppel-like factor 13), rel proteins and scaffolding proteins (in T lymphocytes)

  • In T lymphocytes, acetylation, phosphorylation and methylation of chromatin are key regulators of RANTES (CCL5) expression

  • Understanding of the complex mechanisms that control expression of chemokines such as RANTES (CCL5) is driving the rational design of new therapeutics

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Figure 1: RANTES (red ovals) attracts immune cells from the peripheral blood to sites of inflammation
Figure 2: RANTES activity involves a tetramolecular complex
Figure 3: The RANTES promoter was identified by reporter gene and electrophoretic mobility shift assays
Figure 4: Model of molecular interactions involved in RANTES transcription

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References

  1. Ebert LM et al. (2005) Chemokine-mediated control of T cell traffic in lymphoid and peripheral tissues. Mol Immunol 42: 799–809

    Article  CAS  Google Scholar 

  2. Wiedermann CJ et al. (1993) Monocyte haptotaxis induced by the RANTES chemokine. Curr Biol 3: 735–739

    Article  CAS  Google Scholar 

  3. Johnson Z et al. (2005) Multi-faceted strategies to combat disease by interference with the chemokine system. Trends Immunol 26: 268–274

    Article  CAS  Google Scholar 

  4. Coelho AL et al. (2005) Chemokines provide the sustained inflammatory bridge between innate and acquired immunity. Cytokine Growth Factor Rev 16: 553–560

    Article  CAS  Google Scholar 

  5. Schall TJ et al. (1988) A human T cell-specific molecule is a member of a new gene family. J Immunol 141: 1018–1025

    CAS  PubMed  Google Scholar 

  6. Nelson PJ and Krensky AM (2001) Chemokines, chemokine receptors, and allograft rejection. Immunity 14: 377–386

    Article  CAS  Google Scholar 

  7. Nelson PJ and Krensky AM (1998) Chemokines, lymphocytes and viruses: what goes around, comes around. Curr Opin Immunol 10: 265–270

    Article  CAS  Google Scholar 

  8. Wong MM and Fish EN (2003) Chemokines: attractive mediators of the immune response. Semin Immunol 15: 5–14

    Article  CAS  Google Scholar 

  9. Krensky AM (1999) Biology and therapeutic implications of the chemokine RANTES. ACI International 11: 16–21

    Google Scholar 

  10. Song A et al. (2000) Transcriptional regulation of RANTES expression in T lymphocytes. Immunol Rev 177: 236–245

    Article  CAS  Google Scholar 

  11. Jongstra J et al. (1987) The isolation and sequence of a novel gene from a human functional T cell line. J Exp Med 165: 601–614

    Article  CAS  Google Scholar 

  12. Clayberger C and Krensky AM (2003) Granulysin. Curr Opin Immunol 15: 560–565

    Article  CAS  Google Scholar 

  13. Pattison J et al. (1994) RANTES chemokine expression in cell-mediated transplant rejection of the kidney. Lancet 343: 209–211

    Article  CAS  Google Scholar 

  14. Zheng G et al. (2005) The role of tubulointerstitial inflammation. Kidney Int (Suppl 94): S96–S100

    Article  Google Scholar 

  15. Song A et al. (1999) RFLAT-1: a new zinc finger transcription factor that activates RANTES gene expression in T lymphocytes. Immunity 10: 93–103

    Article  Google Scholar 

  16. Ortiz BD et al. (1996) Kinetics of transcription factors regulating the RANTES chemokine gene reveal a developmental switch in nuclear events during T-lymphocyte maturation. Mol Cell Biol 16: 202–210

    Article  CAS  Google Scholar 

  17. Ortiz BD et al. (1997) Switching gears during T-cell maturation: RANTES and late transcription. Immunol Today 18: 468–471

    Article  CAS  Google Scholar 

  18. Nikolcheva T et al. (2002) A translational rheostat for RFLAT-1 regulates RANTES expression in T lymphocytes. J Clin Invest 110: 119–126

    Article  CAS  Google Scholar 

  19. Imataka H et al. (1994) Cell-specific translational control of transcription factor BTEB expression: the role of an upstream AUG in the 5′-untranslated region. J Biol Chem 269: 20668–20673

    CAS  PubMed  Google Scholar 

  20. Ahn Y-T et al. Dynamics of chromatin remodeling regulate late expression of the chemokine RANTES. Mol Cell Biol 27: 253–266

  21. Rekdal C et al. (2000) The nuclear factor SPBP contains different functional domains and stimulates the activity of various transcriptional activators. J Biol Chem 275: 40288–40300

    Article  CAS  Google Scholar 

  22. Xia M et al. (1996) Stimulus specificity of matrix metalloproteinase dependence of human T cell migration through a model basement membrane. J Immunol 156: 160–167

    CAS  PubMed  Google Scholar 

  23. Miyamoto NG et al. (2000) Interleukin-1β induction of the chemokine RANTES promoter in the human astrocytoma line CH235 requires both constitutive and inducible transcription factors. J Neuroimmunol 105: 78–90

    Article  CAS  Google Scholar 

  24. Krensky AM et al. (1990) T-lymphocyte-antigen interactions in transplant rejection. N Engl J Med 322: 510–517

    Article  CAS  Google Scholar 

  25. Li S et al. (2005) Anti-inflammatory effect of fibrate protects from cisplatin-induced ARF. Am J Physiol Renal Physiol 289: F469–F480

    Article  CAS  Google Scholar 

  26. Schadde E et al. (2000) Expression of chemokines and their receptors in nephrotoxic serum nephritis. Nephrol Dial Transplant 15: 1046–1053

    Article  CAS  Google Scholar 

  27. Roson MI et al. (2006) Acute sodium overload produces renal tubulointerstitial inflammation in normal rats. Kidney Int 70: 1439–1446

    Article  CAS  Google Scholar 

  28. Danoff TM (1998) Chemokines in interstitial injury. Kidney Int 53: 1807–1808

    Article  CAS  Google Scholar 

  29. Kimmel PL et al. (2003) Upregulation of MHC class II, interferon-α and interferon-γ receptor protein expression in HIV-associated nephropathy. Nephrol Dial Transplant 18: 285–292

    Article  CAS  Google Scholar 

  30. Hertting O et al. (2003) Enhanced chemokine response in experimental acute Escherichia coli pyelonephritis in IL-1β-deficient mice. Clin Exp Immunol 131: 225–233

    Article  CAS  Google Scholar 

  31. Crisman JM et al. (2001) Chemokine expression in the obstructed kidney. Exp Nephrol 9: 241–248

    Article  CAS  Google Scholar 

  32. Vielhauer V et al. (2001) Obstructive nephropathy in the mouse: progressive fibrosis correlates with tubulointerstitial chemokine expression and accumulation of CC chemokine receptor 2- and 5-positive leukocytes. J Am Soc Nephrol 12: 1173–1187

    CAS  PubMed  Google Scholar 

  33. Anders HJ et al. (2003) CC chemokine ligand 5/RANTES chemokine antagonists aggravate glomerulonephritis despite reduction of glomerular leukocyte infiltration. J Immunol 170: 5658–5666

    Article  CAS  Google Scholar 

  34. Anders HJ et al. (2001) Chemokine and chemokine receptor expression during initiation and resolution of immune complex glomerulonephritis. J Am Soc Nephrol 12: 919–931

    CAS  PubMed  Google Scholar 

  35. Furuichi K et al. (2000) Distinct expression of CCR1 and CCR5 in glomerular and interstitial lesions of human glomerular diseases. Am J Nephrol 20: 291–299

    Article  CAS  Google Scholar 

  36. Cockwell P et al. (1998) In situ analysis of C–C chemokine mRNA in human glomerulonephritis. Kidney Int 54: 827–836

    Article  CAS  Google Scholar 

  37. Chan RW et al. (2006) Messenger RNA expression of RANTES in the urinary sediment of patients with lupus nephritis. Nephrology (Carlton) 11: 219–225

    Article  CAS  Google Scholar 

  38. Ye DQ et al. (2005) Polymorphisms in the promoter region of RANTES in Han Chinese and their relationship with systemic lupus erythematosus. Arch Dermatol Res 297: 108–113

    Article  CAS  Google Scholar 

  39. Wornle M et al. (2006) Novel role of toll-like receptor 3 in hepatitis C-associated glomerulonephritis. Am J Pathol 168: 370–385

    Article  Google Scholar 

  40. Wagrowska-Danilewicz M et al. (2005) CC chemokines and chemokine receptors in IgA nephropathy (IgAN) and in non-IgA mesangial proliferative glomerulonephritis (MesProGN): the immunohistochemical comparative study. Pol J Pathol 56: 121–126

    CAS  PubMed  Google Scholar 

  41. Lim CS et al. (2001) Th1/Th2 predominance and proinflammatory cytokines determine the clinicopathological severity of IgA nephropathy. Nephrol Dial Transplant 16: 269–275

    Article  CAS  Google Scholar 

  42. Strehlau J et al. (2002) Activated intrarenal transcription of CTL-effectors and TGF-β1 in children with focal segmental glomerulosclerosis. Kidney Int 61: 90–95

    Article  CAS  Google Scholar 

  43. Mlynarski WM et al. (2005) Risk of diabetic nephropathy in type 1 diabetes is associated with functional polymorphisms in RANTES receptor gene (CCR5): a sex-specific effect. Diabetes 54: 3331–3335

    Article  CAS  Google Scholar 

  44. Wang SN et al. (2000) Role of glomerular ultrafiltration of growth factors in progressive interstitial fibrosis in diabetic nephropathy. Kidney Int 57: 1002–1014

    Article  CAS  Google Scholar 

  45. Mezzano SA et al. (2000) Overexpression of chemokines, fibrogenic cytokines, and myofibroblasts in human membranous nephropathy. Kidney Int 57: 147–158

    Article  CAS  Google Scholar 

  46. Le Berre L et al. (2005) Renal macrophage activation and Th2 polarization precedes the development of nephrotic syndrome in Buffalo/Mna rats. Kidney Int 68: 2079–2090

    Article  CAS  Google Scholar 

  47. Torheim EA et al. (2005) Increased expression of chemokines in patients with Wegener's granulomatosis—modulating effects of methylprednisolone in vitro. Clin Exp Immunol 140: 376–383

    Article  CAS  Google Scholar 

  48. Zhou Y et al. (2003) Relative importance of CCR5 and antineutrophil cytoplasmic antibodies in patients with Wegener's granulomatosis. J Rheumatol 30: 1541–1547

    CAS  PubMed  Google Scholar 

  49. Coulomb-L'Hermine A et al. (2001) Expression of the chemokine RANTES in pulmonary Wegener's granulomatosis. Human Pathol 32: 320–326

    Article  CAS  Google Scholar 

  50. Liu B-C et al. (2006) Application of antibody array technology in the analysis of urinary cytokine profiles in patients with chronic kidney disease. Am J Nephrol 26: 483–490

    Article  CAS  Google Scholar 

  51. Pawlak K et al. (2004) Hepatitis intensified oxidative stress, MIP-1β and RANTES plasma levels in uraemic patients. Cytokine 28: 197–204

    Article  CAS  Google Scholar 

  52. Pawlak K et al. (2004) Oxidative stress influences CC-chemokine levels in hemodialyzed patients. Nephron Physiol 96: 105–112

    Article  Google Scholar 

  53. Corsi MM et al. (1999) RANTES and MCP-1 chemokine plasma levels in chronic renal transplant dysfunction and chronic renal failure. Clin Biochem 32: 455–460

    Article  CAS  Google Scholar 

  54. Zheng F et al. (2004) The glomerulosclerosis of aging in females: contribution of the proinflammatory mesangial cell phenotype to macrophage infiltration. Am J Pathol 165: 1789–1798

    Article  CAS  Google Scholar 

  55. Ruster M et al. (2004) Differential expression of beta-chemokines MCP-1 and RANTES and their receptors CCR1, CCR2, CCR5 in acute rejection and chronic allograft nephropathy of human renal allografts. Clin Nephrol 61: 30–39

    Article  CAS  Google Scholar 

  56. Falkensammer C et al. (2006) IL-4 inhibits the TNF-α induced proliferation of renal cell carcinoma (RCC) and cooperates with TNF-α to induce apoptotic and cytokine responses by RCC: implications for antitumor immune responses. Cancer Immunol Immunother 55: 1228–1237

    Article  CAS  Google Scholar 

  57. Kondo T et al. (2004) High expression of chemokine gene as a favorable prognostic factor in renal cell carcinoma. J Urol 171: 2171–2175

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by NIH R37 DK35008-23.

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Authors and Affiliations

  1. in the Division of Immunology and Transplantation Biology in the Department of Pediatrics at Stanford University School of Medicine, AM Krensky is the Shelagh Galligan Professor of Pediatrics and Chief, and Y-T Ahn is a Research Associate, Stanford, CA, USA.,

    Alan M Krensky & Yong-Tae Ahn

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Corresponding author

Correspondence to Alan M Krensky.

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Competing interests

AM Krensky holds patents involving RANTES transcription and KLF13 (US 6,376,240 and US 6,448,039).

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Krensky, A., Ahn, YT. Mechanisms of Disease: regulation of RANTES (CCL5) in renal disease. Nat Rev Nephrol 3, 164–170 (2007). https://doi.org/10.1038/ncpneph0418

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