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Regulation of inflammatory mediators by tetracyclines

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Tetracyclines in Biology, Chemistry and Medicine

Abstract

Tetracyclines (TCs) are a group of antibiotic compounds which possess anti-inflammatory activity bothin vivoandin vitroat pharmacological concentrations. They inhibit the activity of pleiotropic inflammatory mediators such as nitric oxide, prostaglandins, cytokines and MMPs. The mechanism of action of this group of compounds, to inhibit various inflammatory mediators is distinctive. TCs and chemically modified TCs (CMTs) both inhibit nitric oxide synthase (mRNA level), TNFa convertase (enzyme level), which subsequently downregulates nitric oxide, and TNFa production, respectively. TCs and CMTs modulate anti-inflammatory mediators such as IL-10 (mRNA level) and type II IL-1P decoy receptor (secretory enzyme level). Doxycycline and minocycline augment COX-2 (mRNA level)-mediated PGE2production, whereas CMTs preferentially inhibit COX-2 both at mRNA and protein level. These pleiotropic properties of TCs and CMTs make them candidate drugs for complex multifactoral inflammatory diseases.

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References

  1. Golub LM, Ramamurthy NS, McNamara TF, Greenwald RA, Rifkin B (1991) Tetracyclines inhibit connective-tissue breakdown - new therapeutic implications for an old family of drugs. Crit Rev Oral Biol Med 2: 297–322

    PubMed  CAS  Google Scholar 

  2. Golub LM, Suomalainen K, Sorsa T (1992) Host modulation with tetracyclines and their chemically modified analogues. Curr Opin Dent 2: 80–90

    PubMed  CAS  Google Scholar 

  3. Uitto VJ, Firth JD, Nip L, Golub LM (1994) Doxycycline and chemically modified tetracyclines inhibit gelatinase A (MMP-2) gene-expression in human skin keratinocytes. Ann N Y Acad Sci 732: 140–151

    Article  PubMed  CAS  Google Scholar 

  4. DeClerck YA, Shimada H, Taylor SM, Langley KE (1994) Matrix metalloproteinases and their inhibitors in tumor progression. Ann N YAcad Sci 732: 222–232

    Article  CAS  Google Scholar 

  5. Rifkin B, Vernillo AT, Golub LM, Ramamurthy NS (1994) Modulation of bone resorption by tetracyclines. Ann NYAcad Sci 732: 165–180

    Article  CAS  Google Scholar 

  6. Maragoudakis ME, Peristeris P, Missirlis E, Aletras A, Andriopoulou P, Haralabopoulos G (1994) Inhibition of angiogenesis by anthracyclines and titanocene dichloride. Ann N Y Acad Sci 732: 280–293

    Article  PubMed  CAS  Google Scholar 

  7. Amin AR, Attur MG, Abramson SB (1999) Regulation of nitric oxide and inflammatory mediators in human osteoarthritis-affected cartilage: implication for pharmacological intervention. In: GM Rubanyi (ed.): The Pathophysiology and Clinical Applications of Nitric Oxide. Harwood Academic Publishers, Richmond, CA, 397–412

    Chapter  Google Scholar 

  8. Nathan C (1997) Inducible nitric oxide synthase: what difference does it make? J Clin Invest 100: 2417–2423

    Article  PubMed  CAS  Google Scholar 

  9. Belmont HM, Amin AR, Abramson SB (1997) Nitric oxide in systemic lupus erythematosus. In: GM Kammer and GC Tsokos (eds): Lupus: Molecular and Cellular Pathogenesis. Humana Press, Totowa, NJ, 21–42

    Google Scholar 

  10. Milano S, Arcoleo F, D’Agostino P, Cillari E (1997) Intraperitoneal injection of tetracyclines protects mice from lethal endotoxemia downregulating inducible nitric oxide synthase in various organs and cytokine and nitrate secretion in blood. Antimicrob Agents Chemother 41: 117–121

    PubMed  CAS  Google Scholar 

  11. Hanyu T, Chotanaphuti T, Arai K, Tanaka T, Takahashi HE (1999) Histomorphometric assessment of bone changes in rats with type II collagen-induced arthritis. Bone 24: 485–490

    Article  PubMed  CAS  Google Scholar 

  12. Yu LPJ, Smith GNJ, Brandt KD, Myers SL, O’Connor BL, Brandt DA (1992) Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline. Arthritis Rheum 35: 1150–1159

    Article  PubMed  Google Scholar 

  13. TeKoppele JM, Beekman B, Verzijl N, Koopman JL, DeGroot J, Bank RA (1998) Doxycycline inhibits collagen synthesis by differentiated articular chondrocytes. Adv Dent Res 12: 63–67

    Article  PubMed  CAS  Google Scholar 

  14. Amin AR, Di Cesare P, Vyas P, Attur MG, Tzeng E, Billiar TR, Stuchin SA, Abramson SB (1995) The expression and regulation of nitric oxide synthase in human osteoarthritis-affected chondrocytes: Evidence for up-regulated neuronal nitric oxide synthase. J Exp Med 182: 2097–2102

    Article  PubMed  CAS  Google Scholar 

  15. Amin AR, Abramson SB (1998) The role of nitric oxide in articular cartilage breakdown in osteoarthrtis. Curr Opin Rheumatol 10: 263–268

    Article  PubMed  CAS  Google Scholar 

  16. Amin AR, Attur M, Abramson SB (1999) Nitric oxide synthase and cyclooxygenases: distribution, regulation, and intervention in arthritis. Curr Opin Rheumatol 11: 202–209

    Article  PubMed  CAS  Google Scholar 

  17. Tilley BC, Trentham DE, Neuner R, Kaplan DA, Clegg DO, Leisen JCC, Buckley L, Cooper SM, Duncan H, Pillemer SR et al (1995) Minocycline in rheumatoid arthritis. Ann Intern Med 122: 81–89

    PubMed  CAS  Google Scholar 

  18. Amin AR, Patel RN, Thakker GD, Lowenstein CJ, Attur MG, Abramson SB (1997) Post-transcriptional regulation of inducible nitric oxide synthase mRNA in murine macrophages by doxycyclines and chemically modified tetracyclines. FEBS Lett 410: 259–264

    Article  PubMed  CAS  Google Scholar 

  19. Tractman H, Futterweit S, Greenwald RA, Moak SA, Singhal P, Franki N, Amin AR (1996) Chemically modified tetracyclines inhibit inducible nitric oxide synthase expression and nitric oxide production in cultured rat mesengial cells. Biochem Biophys Res Commun 229: 243–248

    Article  Google Scholar 

  20. D’Agostino P, La RM, Barbera C, Arcoleo F, Di BG, Milano S, Cillari E (1998) Doxycycline reduces mortality to lethal endotoxemia by reducing nitric oxide synthesis via an interleukin-l0independent mechanism. J Infect Dis 177: 489–492

    Article  PubMed  Google Scholar 

  21. Farrell AJ, Blake DR, Palmer RM, Moncada S (1992) Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases. Ann Rheum Dis 51: 1219–1222

    Article  PubMed  CAS  Google Scholar 

  22. Perkins DJ, St Misukonis MA, Weinberg JB (1998) Reduction of NOS2 overexpression in rheumatoid arthritis patients treated with anti-tumor necrosis factor alpha monoclonal antibody (cA2). Arthritis Rheum 41: 2205–2210

    Article  PubMed  CAS  Google Scholar 

  23. Davies P, Maclntyre DE (1992) Prostaglandins and inflammation. In: JI Gallin, IM Goldstein, R Snyderman (eds): Basic principles and clinical correlates. Raven Press, New York, 123–138

    Google Scholar 

  24. Crofford LJ (1997) COX-1 and COX-2 tissue expression: implications and predictions. J Rheumatol 24 Suppl 49: 15–19

    CAS  Google Scholar 

  25. Wu KK (1995) Inducible cyclooxygenase and nitric oxide synthase. Adv Pharmacol 33: 179–207

    Article  PubMed  CAS  Google Scholar 

  26. Bombardier S, Cattani P, Giabattoni G, Di Munno O, Paero G, Patron C, Pinca E, Pugliese F (1981) The synovial prostaglandin system in chronic inflammatory arthritis: differential effects of steroidal and non-steroidal anti-inflammatory drugs. Brit J Pharmacol 73: 893–901

    Article  Google Scholar 

  27. Davies P, Bailey PJ, Goldenberg MM, Ford-Hutchinson AW (1984) The role of arachidonic acid oxygenation products in pain and inflammation. Annu Rev Immunol 2: 335–357

    Article  PubMed  CAS  Google Scholar 

  28. Robinson DR, Tashjian AH, Levine L (1975) Prostaglandin-stimulated bone resportion by rheumatoid synovia. A possible mechanism for bone destruction in rheumatoid arthritis. J Clin Invest 56: 1181–1188

    Article  PubMed  CAS  Google Scholar 

  29. Amin AR, Dave M, Attur M, Abramson B (2000) COX-2, NO and cartilage damage and repair. Curr Rheumatoll Rep 2: 447–453

    Article  CAS  Google Scholar 

  30. Seftor EA, Seftor RE, Nieva DR, Hendrix MJ (1998) Application of chemically modified tetracyclines (CMTs) in experimental models of cancer and arthritis. Adv Dent Res 12: 103–110

    Article  PubMed  CAS  Google Scholar 

  31. Seftor RE, Seftor EA, De LJ, Kleiner DE, Leferson J, Stetler-Stevenson WG, McNamara TF, Golub LM, Hendrix MJ (1998) Chemically modified tetracyclines inhibit human melanoma cell invasion and metastasis. Clin Exp Metastasis 16: 217–225

    Article  PubMed  CAS  Google Scholar 

  32. Patel RN, Attur MG, Dave MN, Patel IV, Stuchin SA, Abramson SB, Amin AR (1999) A novel mechanism of action of chemically modified tetracyclines: inhibition of COX-2-mediated prostaglandin E2 production. J Immunol 163: 3459–3467

    PubMed  CAS  Google Scholar 

  33. Vassalli P (1992) The pathophysiology of tumor necrosis factors. Annu Rev Immunol 10: 411–452

    Article  PubMed  CAS  Google Scholar 

  34. Tracey KJ, Cerami A (1993) Tumor necrosis factor, other cytokines and disease. Annu Rev Cell Virol 9: 317–343

    Article  CAS  Google Scholar 

  35. Feldmann M, Brennan FM, Williams RO, Elliott MJ, Maini RN (1996) Cytokine expression and networks in rheumatoid arthritis: rationale for anti-TNFa antibody therapy and its mechanism of action. J Inflamm 47: 90–96

    CAS  Google Scholar 

  36. Tracey KJ, Cerami A (1994) Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu Rev Med 45: 491–503

    Article  PubMed  CAS  Google Scholar 

  37. Gearing AJH, Beckett P, Christodoulo M, Churchill M, Clements J, Davidson AH, Drummond AH, Galloway WA, Gilbert R, Gordon JL et al (1994) Processing of tumor necrosis factor-a precursor metalloproteinases. Nature 370: 555–557

    Article  PubMed  CAS  Google Scholar 

  38. Mohler KM, Sleath PR, Fitzner JN, Cerretti D, Alderson MR, Kerwar SS, Torrance DS, OttenEvans C, Greenstreet T, Weerawama K et al (1994) Protection against a lethal dose of endotoxin by an inhibitor of tumor necrosis factor processing. Nature 370: 218–220

    Article  PubMed  CAS  Google Scholar 

  39. Moss M, Catherine Jin S-L, Milla ME, Burkhart W, Luke Carter H, Chen W-J, Clay WC, Didsbury JR, Hassler D, Hoffman CR et al (1997) Cloning of a disintegrin metalloproteinase that processes precursor tumor-necrosis factor-a. Nature 385: 733–736

    Article  PubMed  CAS  Google Scholar 

  40. Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner B, Stocking KL, Reddy P, Srinivasan S et al (1997) A metalloproteinase disintegrin that releases tumor-necrosis factor-a from cells. Nature 385: 729–733

    Article  PubMed  CAS  Google Scholar 

  41. Patel IR, Attur MG, Patel RN, Stuchin SA, Abagyan RA, Abramson SB, Amin AR (1998) TNF-a convertase from human arthritis-affected cartilage: Isolation of cDNA by differential display, expression of the active enzyme, and regulation of TNF-a. J Immunol 160: 4570–4579

    PubMed  CAS  Google Scholar 

  42. Doedens JR, Black RA (2000) Stimulation-induced down-regulation of tumor necrosis factor-alpha converting enzyme. J Biol Chem 275: 14 598–14 607

    Article  CAS  Google Scholar 

  43. Peschon JJ, Slack JL, Reddy P, Stocking KL, Sunnarborg SW, Lee DC, Russell WE, Castner BJ, Johnson RS, Fitzner JN et al (1998) An essential role for ectodomain shedding in mammalian development. Science 282: 1281–1284

    Article  PubMed  CAS  Google Scholar 

  44. Glaser KB, Falduto M, Metzer R, Pederson T, Pease L, Shiosaki K, Morgan DW (1997) Expression, release, and regulation of human TNFa from stable transfectants of HEK-293 cells. Inflamm Res 46 (Supp12): S127–S128

    Article  PubMed  CAS  Google Scholar 

  45. Jeong J-Y, Jue D-M (1997) Chloroquine inhibits processing of tumor necrosis factor in lipopolysaccharide-stimulated RAW 264.7 macrophages. J Immunol 158: 4901–4907

    PubMed  CAS  Google Scholar 

  46. Shapira L, Houri Y, Barak V, Soskolne WA, Halabi A, Stabholz A (1997) Tetracycline inhibits porphyromonas gingivalis lipopolysaccharide-induced lesions in vivo and TNF alpha processing in vitro. J Periodont Res 32 (1 Pt 2): 183–188

    Article  PubMed  CAS  Google Scholar 

  47. Hawkins D, MacKay R, MacKay S, Moldawer L (1998) Human interleukin-10 suppresses production of inflammatory mediators by LPS-stimulated equine peritoneal macrophages. Vet Immunol Immunopathol 66: 1–10

    Article  PubMed  CAS  Google Scholar 

  48. Ritchlin C, Haas-Smith S, Schwarz E, Greenwald R (2000) Minocycline but not doxycycline upregulates IL-10 production in human synoviocytes, mononuclear cells and synovial explants. ACR 64th Annual Scientific Meeting

    Google Scholar 

  49. Attur M, Dave M, Cipolletta C, Kang P, Goldring M, Patel I, Abramson S, Amin A (2000) Reversal of autocrine and paracrine effects of IL-1 in human arthritis by type II IL-1 decoy receptor: Potential for pharmacological intervention. J Biol Chem 275: 40307–40315

    Article  PubMed  CAS  Google Scholar 

  50. Nieman G, Searles B, Carney D, McCann U, Schiller H, Lutz C, Finck C, Gatto LA, Hodell M, Picone A (1999) Systemic inflammation induced by cardiopulmonary bypass: A review of pathogenesis and treatment. J Extra-Corp Technol 31: 202–210

    CAS  Google Scholar 

  51. Shah PK (1999) Targeting the proteolytic arsenal of neutrophils. A promising approach for post-pump syndrome and ARDS. Circulation 100: 333–334

    Article  PubMed  CAS  Google Scholar 

  52. Amin AR, Attur MG, Patel RN, Thakker GD, Marshall PJ, Rediske J, Abramson SB (1997) Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage: Influence of nitric oxide. J Clin Invest 99: 1231–1237

    Article  PubMed  CAS  Google Scholar 

  53. Attur M, Patel R, Patel P, Abramson S, Amin A (1999) Tetracycline up-regulates COX-2 expression and prostaglandin E2 production independent of its effect on nitric oxide. J Immunol 162: 3160–3167

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Rheumatology, Hospital for Joint Diseases, NYU School of Medicine, 301 E. 17th St., Room 1600, New York, NY, 10003, USA

    Mukundan G. Attur, Mandar N. Dave, Nirupama Mohandas, Indravadan R. Patel, Steven B. Abramson & Ashok R. Amin

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  1. Mukundan G. Attur
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  2. Mandar N. Dave
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  3. Nirupama Mohandas
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  4. Indravadan R. Patel
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  5. Steven B. Abramson
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  6. Ashok R. Amin
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Editor information

Editors and Affiliations

  1. Paratek Pharmaceuticals, 75 Kneeland St., Boston, MA, 02111, USA

    Mark Nelson

  2. Lehrstuhl für Mikrobiologie, Friedrich-Alexander Universität, Erlangen-Nürnberg Staudstr. 5, Erlangen, D-91058, Germany

    Wolfgang Hillen

  3. Division of Rheumatology, Long Island Jewish Medical Center, Suite 107 410 Lakeville Rd, New Hyde Park, NY, 11040, USA

    Robert A. Greenwald

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© 2001 Springer Basel AG

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Attur, M.G., Dave, M.N., Mohandas, N., Patel, I.R., Abramson, S.B., Amin, A.R. (2001). Regulation of inflammatory mediators by tetracyclines. In: Nelson, M., Hillen, W., Greenwald, R.A. (eds) Tetracyclines in Biology, Chemistry and Medicine. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8306-1_13

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  • DOI: https://doi.org/10.1007/978-3-0348-8306-1_13

  • Publisher Name: Birkhäuser, Basel

  • Print ISBN: 978-3-0348-9511-8

  • Online ISBN: 978-3-0348-8306-1

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