Effect of Corticosterone Pretreatment on the Production of LPS-Induced Inflammatory Mediators in RAW 264.7 Cells

RAW 264.7 Cell에서 리포폴리사카라이드로 유도된 염증성 매개인자들의 생산에 있어서 Corticosterone 전처리 효과

  • 채병숙 (우석대학교 약학대학 약학과)
  • Received : 2015.07.20
  • Accepted : 2015.08.26
  • Published : 2015.10.31


Glucocorticoids are known to have anti-inflammatory effect. To investigate whether corticosterone pretreatment enhances or not lipopolysaccharide (LPS)-induced production of inflammatory mediators, RAW 264.7 cells were pretreated with various concentrations of corticosterone for 24 h and then cultured without corticosterone in the presence or absence of LPS. Our results demonstrated that LPS remarkably increased production of TNF-${\alpha}$, IL-6, IL-$1{\beta}$, vascular endothelial growth factor (VEGF), and NO (nitric oxide). Corticosterone pretreatment significantly attenuated LPS-induced production of TNF-${\alpha}$, IL-$1{\beta}$, and VEGF, while significantly enhanced IL-6 and NO. These findings suggest that corticosterone pretreatment may contribute to LPS-induced inflammatory responses in macrophages via pro- and anti-inflammatory imbalance of inflammatory mediators.


  1. Chrousos, G. P. : The HPA axis and the stress response. Endocr. Res. 26, 513 (2000).
  2. Wilckens, T. : Glucocorticoids and immune function: physiological relevance and pathogenic potential of hormonal dysfunction. Trends Pharmacol. Sci. 16, 193 (1995).
  3. Annane, D., Bellissant, E. and Bollaert, P. E. : Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA 301, 2362 (2009).
  4. Chrousos, G. P. : The stress response and immune function: clinical implications. The 1999 Novera H. Spector Lecture. Ann. N. Y. Acad. Sci. 917, 38 (2000).
  5. Chrousos, G. P. : Stress, chronic inflammation, and emotional and physical well-being: concurrent effects and chronic sequelae. J. Allergy Clin. Immunol. 106(5 Suppl), S275 (2000).
  6. Constantinopoulos, P., Michalaki, M., Kottorou, A., Habeos, I., Psyrogiannis, A., Kalfarentzos, F. and Kyriazopoulou, V. : Cortisol in tissue and systemic level as a contributing factor to the development of metabolic syndrome in severely obese patients. Eur. J. Endocrinol. 172, 69 ( 2015).
  7. van Raalte, D. H., Ouwens, D. M. and Diamant, M. : Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options? Eur. J. Clin. Invest. 39, 81 (2009).
  8. Pasquali, R., Vicennati, V., Cacciari, M. and Pagotto, U. : The hypothalamic-pituitary-adrenal axis activity in obesity and the metabolic syndrome. Ann. N. Y. Acad. Sci. 1083, 111 (2006).
  9. Wolf, G. : Glucocorticoids in adipocytes stimulate visceral obesity. Nutr. Rev. 60(5 Pt 1), 148 (2002).
  10. Chrousos, G. P. : The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N. Engl. J. Med. 332, 1351 (1995).
  11. Morrison, D. C. and Ryan J. L. : Bacterial endotoxins and host immune responses. Adv. Immunol. 28, 293 (1979).
  12. Rojas, M., Woods, C. R., Mora, A. L., Xu, J. and Brigham, K. L. : Endotoxin-induced lung injury in mice: structural, functional, and biochemical responses. Am. J. Physiol. Lung Cell Mol. Physiol. 288, L333 (2005).
  13. Bastard, J. P., Maachi, M., Lagathu, C., Kim, M. J., Caron, M., Vidal, H., Capeau, J. and Feve, B. : Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur. Cytokine Netw. 17, 4 (2006).
  14. Kanczkowski, W., Sue, M., Zacharowski, K., Reincke, M. and Bornstein, S. R. : The role of adrenal gland microenvironment in the HPA axis function and dysfunction during sepsis. Mol. Cell. Endocrinol. S0303-7207, 00422 (2014).
  15. Briegel, J. : Cortisol in critically ill patients with sepsis--physiological functions and therapeutic implications. Wien. Klin. Wochenschr. 114(Suppl 1), 9 (2002).
  16. Sprung, C. L., Annane, D., Keh, D., Moreno, R., Singer, M., Freivogel, K., Weiss, Y. G., Benbenishty, J., Kalenka, A., Forst, H., Laterre, P. F., Reinhart, K., Cuthbertson, B. H., Payen, D. and Briegel, J. : CORTICUS Study Group : Hydrocortisone therapy for patients with septic shock. N. Engl. J. Med. 358, 111 (2008).
  17. Smyth, G. P., Stapleton, P. P., Freeman, T. A., Concannon, E. M., Mestre, J. R., Duff, M., Maddali, S. and Daly, J. M. : Glucocorticoid pretreatment induces cytokine overexpression and nuclear factor-kappaB activation in macrophages. J. Surg. Res. 116, 253 (2004).
  18. Fantuzzi, G., Demitri, M. T. and Ghezzi, P. : Differential effect of glucocorticoids on tumour necrosis factor production in mice: up-regulation by early pretreatment with dexamethasone. Clin. Exp. Immunol. 96, 166 (1994).
  19. Yeager, M. P., Rassias, A. J., Pioli, P. A., Beach, M. L., Wardwell, K., Collins, J. E., Lee, H. K. and Guyre, P. M. : Pretreatment with stress cortisol enhances the human systemic inflammatory response to bacterial endotoxin. Crit. Care Med. 37, 2727 (2009).
  20. Barber, A. E., Coyle, S. M., Marano, M. A., Fischer, E., Calvano, S. E., Fong, Y., Moldawer, L. L. and Lowry, S. F. : Glucocorticoid therapy alters hormonal and cytokine responses to endotoxin in man. J. Immunol. 150, 1999 (1993).
  21. Morrow, L. E., McClellan, J. L., Conn, C. A. and Kluger, M. J. : Glucocorticoids alter fever and IL-6 responses to psychological stress and to lipopolysaccharide. Am. J. Physiol. 264(5 Pt 2), R1010 (1993).
  22. Zhou, D., Kusnecov, A. W., Shurin, M. R., DePaoli, M. and Rabin, B. S. : Exposure to physical and psychological stressors elevates plasma interleukin 6: relationship to the activation of hypothalamic-pituitary-adrenal axis. Endocrinology 133, 2523 (1993).
  23. Permana P. A., Menge, C. and Reaven, P. D. : Macrophage-secreted factors induce adipocyte inflammation and insulin resistance. Biochem. Biophys. Res. Commun. 341, 507 (2006).
  24. Tack, C. J., Stienstra, R., Joosten, L. A. and Netea, M. G. : Inflammation links excess fat to insulin resistance: the role of the interleukin-1 family. Immunol. Rev. 249, 239 (2012).
  25. Snyers, L., De Wit, L. and Content, J. : Glucocorticoid up-regulation of high-affinity interleukin 6 receptors on human epithelial cells. Proc. Natl. Acad. Sci. USA 87, 2838 (1990).
  26. Puchner, A. and Bluml, S. : IL-6 blockade in chronic inflammatory diseases. Wien. Med. Wochenschr. 165, 14 (2014).
  27. Shacter, E., Arzadon, G. K. and Williams, J. : Elevation of interleukin-6 in response to a chronic inflammatory stimulus in mice: Inhibition by Indomethacin. Blood 80, 194 (1992).
  28. Kim, H. J., Higashimori, T., Park, S. Y., Choi, H., Dong, J., Kim, Y. J., Noh, H. L., Cho, Y. R., Cline, G., Kim, J. H., Bachmann, R. A. and Chen, J. : Interleukin-6 and insulin resistance. Vitam. Horm. 80, 613 (2009).
  29. Kiecolt-Glaser, J. K., Preacher, K. J., MacCallum, R. C., Atkinson, C., Malarkey, W. B. and Glaser, R. : Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc. Natl. Acad. Sci. USA 100, 9090 (2003).
  30. Depraetere, S., Willems, J. and Joniau, M. : Stimulation of CRP secretion in HepG2 cells: cooperative effect of dexamethasone and interleukin 6. Agents Actions. 34, 369 (1991).
  31. Mastorakos, G., Weber, J. S., Magiakou, M. A., Gunn, H. and Chrousos, G. P. : Hypothalamic-pituitary-adrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: potential implications for the syndrome of inappropriate vasopressin secretion. J. Clin. Endocrinol. Metab. 79, 934 (1994).
  32. Briancon-Marjollet, A., Pepin, J. L., Weiss, J. W., Levy, P. and Tamisier, R. : Intermittent hypoxia upregulates serum VEGF. Sleep Med. 15, 1425 (2014).
  33. Segi-Nishida, E., Warner-Schmidt, J. L. and Duman, R. S. : Electroconvulsive seizure and VEGF increase the proliferation of neural stem-like cells in rat hippocampus. Proc. Natl. Acad. Sci. USA 105, 11352 (2008).
  34. Koczy-Baron, E. and Kasperska-Zajac, A. : The role of vascular endothelial growth factor in inflammatory processes. Postepy. Hig. Med. Dosw. (Online) 68, 57 (2014).
  35. Tang, X., Yang, Y., Yuan, H., You, J., Burkatovskaya, M. and Amar, S. : Novel transcriptional regulation of VEGF in inflammatory processes. J. Cell. Mol. Med. 17, 386 (2013).
  36. Yano, K., Liaw, P. C., Mullington, J. M., Shih, S. C., Okada, H., Bodyak, N., Kang, P. M., Toltl, L., Belikoff, B., Buras, J., Simms, B. T., Mizgerd, J. P., Carmeliet, P., Karumanchi, S. A. and Aird, W. C. : Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality. J. Exp. Med. 203, 1447 (2006).
  37. Gao, T., Lin, Z. and Jin, X. : Hydrocortisone suppression of the expression of VEGF may relate to toll-like re ceptor (TLR) 2 and 4. Curr. Eye Res. 34, 777 (2009).
  38. Carvalho, L. A., Torre, J. P., Papadopoulos, A. S., Poon, L., Juruena, M. F., Markopoulou, K., Cleare, A. J. and Pariante, C. M. : Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system. J. Affect Disord. 148, 136 (2013).
  39. Perreault, M. and Marette, A. : Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat. Med. 7, 1138 (2001).
  40. Radomski, M. W., Palmer, R. M. J. and Moncada, S. : Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc. Natl. Acad. Sci. USA 87, 10043 (1990).