Induction Mechanism of PD-L1 (Programmed Cell Death-ligand 1) in Sepsis

패혈증에서 PD-L1 (Programmed Cell Death-ligand 1)의 발현 증가 기전

  • Lee, Sang-Min (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute, Medical Research Center, Seoul National University College of Medicine)
  • 이상민 (서울대학교 의과대학 내과학교실 및 폐연구소)
  • Published : 2008.10.30

Abstract

PD-L1 is expressed in a variety of antigen-presenting cells and provides T cell tolerance via ligation with its receptor PD-1 and B7-1 on T cells. Stimulation with lipopolysaccharide (LPS) can increase the level of PD-L1 expression in B cells and macrophages, which suggests that this molecule plays a role in the immunosuppression observed in severe sepsis. The aim of this study was to identify which of the downstream pathways of TLR4 are involved in the up-regulation of PD-L1 by LPS in macrophages. Flow cytometry was used to examine the expression of PD-L1 in RAW 264.7 macrophages stimulated with LPS. The following chemical inhibitors were used to evaluate the role of each pathway: LY294002 for PI3K/Akt, SB202190 for p38 MAPK, and U0126 for MEK. LPS induced the expression of PD-L1 in a time- and dose-dependent manner. Transfection of siRNA for TLR4 suppressed the induction of PD-L1. Pretreatment with LY294002 and SB202190 decreased the level of PD-L1 expression but U0126 did not. Overall, the PI3K/Akt and p38 MAPK pathways are involved in the up-regulation of PD-L1 expression in RAW 264.7 macrophages stimulated with LPS.

Keywords

References

  1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303-10. https://doi.org/10.1097/00003246-200107000-00002
  2. Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987;317:653-8. https://doi.org/10.1056/NEJM198709103171101
  3. Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med 1996;24:1125-8. https://doi.org/10.1097/00003246-199607000-00010
  4. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003;348:138-50. https://doi.org/10.1056/NEJMra021333
  5. Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol 2006;27:195-201. https://doi.org/10.1016/j.it.2006.02.001
  6. Iwai Y, Terawaki S, Ikegawa M, Okazaki T, Honjo T. PD-1 inhibits antiviral immunity at the effector phase in the liver. J Exp Med 2003;198:39-50. https://doi.org/10.1084/jem.20022235
  7. Liang SC, Latchman YE, Buhlmann JE, Tomczak MF, Horwitz BH, Freeman GJ, et al. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol 2003;33:2706-16. https://doi.org/10.1002/eji.200324228
  8. Wiendl H, Mitsdoerffer M, Schneider D, Chen L, Lochmuller H, Melms A, et al. Human muscle cells express a B7-related molecule, B7-H1, with strong negative immune regulatory potential: a novel mechanism of counterbalancing the immune attack in idiopathic inflammatory myopathies. FASEB J 2003;17:1892-4. https://doi.org/10.1096/fj.03-0039fje
  9. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 2007;8:239-45. https://doi.org/10.1038/ni1443
  10. Nishimura H, Minato N, Nakano T, Honjo T. Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int Immunol 1998;10:1563-72. https://doi.org/10.1093/intimm/10.10.1563
  11. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif- carrying immunoreceptor. Immunity 1999;11:141-51. https://doi.org/10.1016/S1074-7613(00)80089-8
  12. Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med 2003;198:63-9. https://doi.org/10.1084/jem.20022125
  13. Guleria I, Khosroshahi A, Ansari MJ, Habicht A, Azuma M, Yagita H, et al. A critical role for the programmed death ligand 1 in fetomaternal tolerance. J Exp Med 2005;202:231-7. https://doi.org/10.1084/jem.20050019
  14. Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, et al. Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A 2004;101:17174-9. https://doi.org/10.1073/pnas.0406351101
  15. Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res 2005;11:2947-53. https://doi.org/10.1158/1078-0432.CCR-04-1469
  16. Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 2002;169: 5538-45. https://doi.org/10.4049/jimmunol.169.10.5538
  17. Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci U S A 2003;100:5336-41. https://doi.org/10.1073/pnas.0931259100
  18. Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet 2005;365:63-78. https://doi.org/10.1016/S0140-6736(04)17667-8
  19. Lee SK, Seo SH, Kim BS, Kim CD, Lee JH, Kang JS, et al. IFN-gamma regulates the expression of B7-H1 in dermal fibroblast cells. J Dermatol Sci 2005;40:95-103. https://doi.org/10.1016/j.jdermsci.2005.06.008
  20. Keir ME, Latchman YE, Freeman GJ, Sharpe AH. Programmed death-1 (PD-1):PD-ligand 1 interactions inhibit TCR-mediated positive selection of thymocytes. J Immunol 2005;175:7372-9. https://doi.org/10.4049/jimmunol.175.11.7372
  21. Saunders PA, Hendrycks VR, Lidinsky WA, Woods ML. PD-L2:PD-1 involvement in T cell proliferation, cytokine production, and integrin-mediated adhesion. Eur J Immunol 2005;35:3561-9. https://doi.org/10.1002/eji.200526347