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Antiinflammatory Effect of Lipocortin 1 in Experimental Arthritis

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Abstract

The glucocorticoid-induced antiinflammatory protein lipocortin 1 is present in arthritic synovium but its ability to regulate joint inflammation has not previously been studied. We investigated the role of lipocortin 1 in the antiinflammatory activity of glucocorticoids in an acute arthritis model induced by intraarticular injection of carrageenan. Compared to control joints (0.09 ± 0.08 × 106 synovial fluid cell count), carrageenan injected joints exhibited marked infiltration of PMN (10.2 ± 0.7 × 106, p < 0.001). Both intraperitoneal (1.0 mg/kg) and intraarticular administration (5 μg) of dexamethasone (DEX) significantly suppressed arthritis severity (p < 0.001 and 0.005, respectively), and the effects of DEX were significantly prevented by intra-articular injection of antilipocortin 1 mAb (p < 0.05). Carrageenan arthritis was also significantly inhibited by intraarticular administration of the N-terminal lipocortin 1 peptide Ac2-26 at doses of 1 or 2 mg/kg (p < 0.01). Intraarticular injection antilipocortin 1 mAb in the absence of DEX also significantly exacerbated arthritis severity (p < 0.005). In vitro treatment of PMN with DEX was associated with significant inhibition of phagocytosis (p < 0.005) and reactive oxygen species (ROS) generation (p < 0.001). Antilipocortin 1 mAb significantly reduced the inhibitory effects of DEX (p < 0.01 and 0.005, respectively). These results demonstrate that lipocortin 1 mediates the effects of exogenous glucocorticoids on neutrophil migration in carrageenan-induced acute arthritis, exerts an endogenous antiinflammatory influence, and mediates glucocorticoid inhibition of neutrophil activation.

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REFERENCES

  1. ZVAIFLER, N. J., and G. S. FIRESTEIN. 1994. Pannus and pannocytes. Alternative models of joint destruction in rheumatoid arthritis. Arthritis Rheum. 37:783–789.

    Google Scholar 

  2. BURMESTER, G. R., B. STUHLMULLER, G. KEYSZER, and R. W. KINNE. 1997. Mononuclear phagocytes and rheumatoid synovitis—Mastermind or workhorse in arthritis. Arthritis Rheum. 40:5–18X.

    Google Scholar 

  3. MORAND, E. F., and N. J. GOULDING. 1993. Glucocorticoids in rheumatoid arthritis—Mediators and mechanisms. Br. J. Rheumatol. 32:816–819.

    Google Scholar 

  4. CHROUSOS, G. P. 1995. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N. Engl. J. Med. 332:1351–1362.

    Google Scholar 

  5. STEPHANOU, A., N. J. SARLIS, R. A. KNIGHT, S. L. LIGHTMAN, and H. S. CHOWDREY. 1992. Glucocorticoid-mediated responses of plasma ACTH and anterior pituitary pro-opiomelanocortin, growth hormone and prolactin mRNAs during adjuvant-induced arthritis in the rat. J. Mol. Endocrinol 9:273–281.

    Google Scholar 

  6. MANCUSO, F., R. J. FLOWER, and M. PERRETTI. 1995. Leukocyte transmigration, but not rolling or adhesion, is selectively inhibited by dexamethasone in the hamster post-capillary venule. Involvement of endogenous lipocortin 1. J. Immunol. 155:377–386.

    Google Scholar 

  7. TESSIER, P. A., P. CATTARUZZI, and S. R. MC COLL. 1996. Inhibition of lymphocyte adhesion to cytokine-activated synovial fibroblasts by glucocorticoids involves the attenuation of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 gene expression. Arthritis Rheum 39:226–234.

    Google Scholar 

  8. KERN, J. A., R. J. LAMB, J. C. REED, R. P. DANIELE, and P. C. NOWELL. 1988. Dexamethasone inhibition of interleukin 1 beta production by human monocytes. Posttranscriptional mechanisms. J. Clin. Invest. 81:237–244.

    Google Scholar 

  9. CROFFORD, L. J., R. L. WILDER, A. P. RISTIMÄKI, H. SANO, E. F. REMMERS, H. R. EPPS, and T. HIA. 1994. Cyclooxygenase-1 and-2 expression in rheumatoid synovial tissues. Effects of interleukin-lbeta, phorbol ester, and corticosteroids. J. Clin. Invest. 93:1095–1101.

    Google Scholar 

  10. SAUER, J., G. K. STALLA, O.-A. MÜLLER, and E. ARZT. 1994. Inhibition of interleukin-2-mediated lymphocyte activation in patients with Cushing's syndrome: A comparison with hypocortisolemic patients. Neuroendocrinology 59:144–151.

    Google Scholar 

  11. SZABO, C., C. THIEMERMANN, C.-C. WU, M. PERRETTI, and J. R. VANE. 1994. Attenuation of the induction of nitric oxide synthase by endogenous glucocorticoids accounts for endotoxin tolerance in vivo. Proc. Natl. Acad. Sci. U.S.A. 91:271–275.

    Google Scholar 

  12. VISHWANATH, B. S., F. J. PREY, M. J. BRADBURY, M. F. DALLMAN, and B. M. FREY. 1993. Glucocorticoid deficiency increases phospholipase A2 activity in rats. J. Clin. Invest. 92:1974–1980.

    Google Scholar 

  13. SWAIRJO, M. A., and B. A. SEATON. 1994. Annexin structure and membrane interactions: a molecular perspective. Annu. Rev. Biophys. Struct. 23:193–213.

    Google Scholar 

  14. PERRETTI, M., and R. J. FLOWER. 1993. Modulation of IL-1-induced neutrophil migration by dexamethasone and lipocortin 1. J. Immunol. 150:992–999.

    Google Scholar 

  15. Wu, C-C., J. D. CROXTALL, M. PERRETTI, C. E. BRYANT, C. THIEMERMANN, R. J. FLOWER, and J. R. VANE. 1995. Lipocortin 1 mediates the inhibition by dexamethasone of the induction by endotoxin of nitric oxide synthase in the rat. Proc. Natl. Acad. Sci. U.S.A. 92:3473–3477.

    Google Scholar 

  16. MARIDONNEAU-PARINI, I., M. ERRASFA, and F. RUSSO-MARIE. 1989. Inhibition of O 2 generation by dexamethasone is mimicked by lipocortin I in alveolar macrophages. J. Clin. Invest. 83:1936–1940.

    Google Scholar 

  17. KIM, K. M., D. K. KIM, Y. M. PARK, C. K. KIM, and D. S. NA. 1994. Annexin-I inhibits phospholipase A2 by specific interaction, not by substrate depletion. FEBS Lett. 343:251–255.

    Google Scholar 

  18. GOULDING, N. J., J. DIXEY, E. F. MORAND, R. DODDS, L. WILKINSON, A. A. PITSILLIDES, and J. C. W. EDWARDS. 1995. Differential expression of annexins-I,-II,-IV and-VI in synovium. Ann. Rheum. Dis. 54:841–845.

    Google Scholar 

  19. MORAND, E. F., P. HUTCHINSON, A. HARGREAVES, N. J. GOULDING, N. W. BOYCE, and S. R. HOLDSWORTH, 1995. Detection of intracellular lipocortin 1 in human leukocyte subsets. Clin. Immunol. Immunopathol. 76:195–202.

    Google Scholar 

  20. PEPINSKY, R. B., L. K. SINCLAIR, I. DOUGAS, C.-M. LIANG, P. LAWTON, and J. L. BROWNING. 1990. Monoclonal antibodies to lipocortin-1 as probes for biological function. FEBS Lett. 261:247–252.

    Google Scholar 

  21. HARRIS, J. G., R. J. FLOWER, and M. PERRETTI. 1995. Alteration of neutrophil trafficking by a lipocortin 1 n-terminus peptide. Eur. J. Pharmacol. 279:149–157.

    Google Scholar 

  22. BOHMER, R. H., L. S. TRINKLE, and J. L. STANECK. 1992. Dose effects of LPS on neutrophils in a whole blood flow cytometric assay of phagocytosis and oxidative burst. Cytometry 13:525–531.

    Google Scholar 

  23. EMMENDORFFER, A., M. HECHT, M. L. LOHMANN-MATTHES, and J. ROESLER. 1990. A fast and easy method to determine the production of reactive oxygen intermediates by human and murine phagocytes using dihydrorhodamine 123. J. Immunol. Methods 131:269–275.

    Google Scholar 

  24. PERRETTI, M., S. K. WHELLER, Q. CHOUDHURY, J. D. CROXTALL, and R. J. FLOWER. 1995. Selective inhibition of neutrophil function by a peptide derived from lipocortin 1 N-terminus. Biochem. Pharmacol. 50:1037–1042.

    Google Scholar 

  25. STERNBERG, E. M., J. M. HILL, G. P. CHROUSOS, T. KAMILARIS, S. J. LISTWAK, P. W. GOLD, and R. L. WILDER. 1989. Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall arthritis susceptible Lewis rats. Proc. Natl. Acad. Sci. U.S.A. 86:2374–2378.

    Google Scholar 

  26. SOLITO, E., G. RAUGEI, M. MELLI, and L. PARENTE. 1991. Dexamethasone induces the expression of the mRNA of lipocortin 1 and 2 and the release of lipocortin 1 and 5 in differentiated, but not undifferentiated U-937 cells. FEBS Lett. 291:238–244.

    Google Scholar 

  27. COMERA, C., and F. RUSSOMARIE. 1995. Glucocorticoid-induced annexin 1 secretion by monocytes and peritoneal leukocytes. Brit. J. Pharmacol. 115:1043–1047.

    Google Scholar 

  28. GOULDING, N. J., J. L. GODOLPHIN, P. R. SHARLAND, S. H. PEERS, M. SAMPSON, P. J. MADDISON, and R. J. FLOWER. 1990. Anti-inflammatory lipocortin 1 production by peripheral blood leucocytes in response to hydrocortisone. Lancet 335: 1416–1418.

    Google Scholar 

  29. MORAND, E. F., C. M. JEFFERISS, J. DIXEY, D. MITRA, and N. J. GOULDING. 1994. Impaired glucocorticoid induction of mononuclear leukocyte lipocortin 1 in rheumatoid arthritis. Arthritis Rheum. 37:207–211.

    Google Scholar 

  30. PERRETTI, M., J. D. CROXTALL, S. K. WHELLER, N. J. GOULDING, R. HANNON, and R. J. FLOWER. 1996. Mobilizing lipocortin 1 in adherent human leukocytes downregulates their transmigration. Nature Medicine 2:1259–1262.

    Google Scholar 

  31. YANG, Y. H., P. HUTCHINSON, M. LEECH, and E. F. MORAND. 1997. Exacerbation of adjuvant arthritis by adrenalectomy is associated with reduced leukocyte lipocortin 1. J. Rheumatol. (in press).

  32. SANTOS, L. L., E. F. MORAND, P. HUTCHINSON, N. W. BOYCE, and S. R. HOLDSWORTH. 1997. Anti-neutrophil monoclonal antibody therapy inhibits the development of adjuvant arthritis. Clin. Exp. Immunol. 107:248–254.

    Google Scholar 

  33. YOUSSEF, P. P., J. CORMACK, C. A. EVILL, D. T. PETER, P. J. R OBERTS-THOMSON, J. M. AHERN, and M. D. SMITH. 1996. Neutrophil trafficking into inflamed joints in patients with rheumatoid arthritis, and the effects of methylprednisolone. Arthritis Rheum. 39:216–225.

    Google Scholar 

  34. VINEGAR, R., J. F. TRUAX, J. L. SELPH, P. R. JOHNSTON, A. L. VENABLE, and K. K. MC KENZIE. 1987. Pathway to carrageenan-induced inflammation in the hind limb of the rat. Fed. Proc. 46:118–126.

    Google Scholar 

  35. WEI, X. Q., I. G. CHARLES, A. SMITH, J. URE, G. J. FENG, F. P. HUANG, D. XU, W. MULLER, S. MONCADA, and F. Y. LIEW. 1995. Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375:408–411.

    Google Scholar 

  36. STICHTENOTH, D. O., J. FAULER, H. ZEIDLER, and J. C. FROLICH. 1995. Urinary nitrate excretion is increased in patients with rheumatoid arthritis and reduced by prednisolone. Ann. Rheum. Dis. 54:820–824.

    Google Scholar 

  37. STENBERG, V. I., M. G. BOULEY, B. M. KATZ, K. J. LEE, and S. S. PARMAR. 1990. Negative control system for inflammation in rats. Agents Actions 29:189–195.

    Google Scholar 

  38. KARALIS, K., L. CROFFORD, R. L. WILDER, and G. P. CHROUSOS. 1995. Glucocorticoid and/or glucocorticoid antagonist effects in inflammatory disease-susceptible Lewis rats and inflammatory disease-resistant Fischer rats. Endocrinology 136:3107–3112.

    Google Scholar 

  39. ROILIDES, E., K. UHLIG, D. VENZON, P. A. PIZZO, and T. J. WALSH. 1993. Prevention of corticosteroid-induced suppression of human polymorphonuclear leukocyte-induced damage of Aspergillus fumigatus hyphae by granulocyte colony-stimulating factor and gamma interferon. Infect. Immun. 61:4870–4877.

    Google Scholar 

  40. LOMAS, D. A., M. IP, A. CHAMBA, and R. A. STOCKLEY. 1991. The effect of in vitro and in vivo dexamethasone on human neutrophil function. Agents Actions 33:279–285.

    Google Scholar 

  41. SCHLAEPFER, D. D., and H. T. HAIGLER. 1987. Characterization of Ca2+dependent phospholipid binding and phosphorylation of lipocortin 1. J. Biol. Chem. 262:6931–6937.

    Google Scholar 

  42. BROWNING, J. L., M. P. WARD, B. P. WALLNER, and R. B. PEPINSKY. 1990. Studies on the structural properties of lipocortin-1 and the regulation of its synthesis by steroids. Prog. Clin. Biol. Res. 349:27–45.

    Google Scholar 

  43. PERRETTI, M. 1994. Lipocortin-derived peptides. Biochem. Pharmacol. 47:931–938.

    Google Scholar 

  44. SANTOS, L., and P. G. TIPPING. 1994, Attenuation of adjuvant arthritis in rats by treatment with oxygen radical scavengers. Immunol. Cell Biol. 72:406–414.

    Google Scholar 

  45. SaKURAI, H., H. KOHSAKA, M. F. LIU, H. HIGASHIYAMA, Y. HIRATA, K. KANNO, I. SAITO, and N. MIYASAKA. 1995. Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides. J. Clin. Invest. 96:2357–2363.

    Google Scholar 

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Yang, Y., Leech, M., Hutchinson, P. et al. Antiinflammatory Effect of Lipocortin 1 in Experimental Arthritis. Inflammation 21, 583–596 (1997). https://doi.org/10.1023/A:1027330021479

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