본문 바로가기
HOME> 논문 > 논문 검색상세

논문 상세정보

p38 Mitogen-Activated Protein Kinase and Extracellular Signal-Regulated Kinase Regulate Nitric Oxide Production and Inflammatory Cytokine Expression in Raw Cells

Choi, Cheol-Hee   (Research Center for Resistant Cells, Department of Pharmacology, College of Medicine, Chosun UniversityUU0001180  ); Kim, Sang-Hyun   (Department of Pharmacology, School of Medicine, Kyungpook National UniversityUU0000096  );
  • 초록

    Background: p38 and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling are thought to have critical role in lipopolysaccharide (LPS)-induced immune response but the molecular mechanism underlying the induction of these signaling are not clear. Methods: Specific inhibitors for p38, SB203580, and for ERK, PD98059 were used. Cells were stimulated by LPS with or without specific MAPK inhibitors. Results: LPS activated inducible nitric oxide synthase (iNOS), subsequent NO productions, and pro-inflammatory cytokine gene expressions (TNF- ${\alpha}$ , IL- $1{\beta}$ , IL-6, and IL-12). Treatment of both SB203580 and PD98059 decreased LPS-induced NO productions. Concomitant decreases in the expression of iNOS mRNA and protein were detected. SB203580 and PD98059 decreased LPS-induced gene expression of IL- $1{\beta}$ and IL-6. SB203580 increased LPS-induced expression of TNF- ${\alpha}$ and IL-12, and reactive oxygen species production, but PD98059 had no effect. Conclusion: These results indicate that both p38 and ERK pathways are involved in LPS-stimulated NO synthesis, and expression of IL- $1{\beta}$ and IL-6. p38 signaling pathways are involved in LPS-induced TNF- ${\alpha}$ and IL-12, and reactive oxygen species plays an important role in these signaling in macrophage.


  • 주제어

    p38 .   ERK .   nitric oxide .   cytokine .   LPS .   ROS.  

  • 참고문헌 (32)

    1. Gross SS, Wolin MS: Nitric oxide: pathophysiological mechanisms. Annu Rev Physiol 57:737-769, 1995 
    2. Nussler AK, Billiar TR: Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol 54:171-178, 1993 
    3. Chen CC, Wang JK: p38 but not p44/42 mitogen-activated protein kinase is required for nitric oxide synthase induction mediated by lipopolysaccharide in RAW 264.7 macrophages. Mol Pharmacol 55:481-488, 1999 
    4. Brook M, Sully G, Clark AR, Saklatvala J: Regulation of tumour necrosis factor alpha mRNA stability by the mitogen-activated protein kinase p38 signalling cascade. FEBS Lett 483:57-61, 2000 
    5. Caivano M, Cohen P: Role of tnitogen-activated protein kinase cascades in mediating lipopolysaccharide-stimulated induction of cyclooxygenase-2 and IL-1 beta in RA W264 macrophages. J Immunol 164:3018-3025, 2000 
    6. Kim SH, Johnson VJ, Sharma RP: Mercury inhibits nitric oxide production but activates proinflammatory cytokine expression in murine macrophage: differential modulation of NF-kappaB and p38 MAPK signaling pathways. Nitric Oxide 7:67-74, 2002 
    7. Marriott JB, Clarke IA, Dalgleish AG: Inhibition of p38 MAP kinase during cellular activation results in IFN-gammadependent augmentation of IL-12 production by human monocytes/ macrophages. Clin Exp Immunol 125:64-70, 2001 
    8. Baldassare JJ, Bi Y, Bellone CJ: The role of p38 mitogenactivated protein kinase in IL-l beta transcription. J Immunol 162:5367-5373, 1999 
    9. Royall JA, Ischiropoulos H: Evaluation of $2^{\prime},7^{\prime}$-dicWoro-fluorescin and dihydrorhodamine 123 as fluorescent probes for intracellular H2O2 in cultured endothelial cells. Arch Biochem Biophys 302:348-355, 1993 
    10. Seger R and Krebs EG: The MAPK signaling cascade. FASEB J 9:726-735, 1995 
    11. Zhang JS, Feng WG, Li CL, Wang XY, Chang ZL: NFkappa B regulates the LPS-induced expression of interleukin 12 p40 in murine peritoneal macrophages: roles of PKC, PKA, ERK, p38 MAPK, and proteasome. Cell Immunol 204: 38-45, 2000 
    12. MathewJS, Sharma RP: Effect of all.rransrctinoic acid on cytokine production in a murine macrophage cell line. Int J Immunopharmacol 22:693-706, 2000 
    13. Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR: A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA 92:7686-76869, 1995 
    14. VaIledor AF, Comalada M, Xaus J, Celada A: The differential time-course of extracellular-regulated kinase activity correlates with the macrophage response toward proliferation or activation. J Biol Chem 275:7403-7409, 2000 
    15. Hsu HY, Wen MH: Lipopolysaccharide-mediated reactive oxygen species and signal transduction in the regulation of interleukin-1 gene expression. J Biol Chem 277:22131-22129, 2002 
    16. Beyaert R, Cuenda A, Vanden Berghe W, Plaisance S, Lee JC, Haegeman G, Cohen P, Fiers W: The p38/RK mitogenactivated protein kinase pathway regulates interleukin-6 synthesis response to tumor necrosis factor. EMBO J 15:1914-1923, 1996 
    17. Lahti A, Kankaanranta H, Moilanen E: P38 mitogen-activated protein kinase inhibitor SB203580 has a bi-directional effect on iNOS expression and NO production. Eur J Pharmacal 454:115-123, 2002 
    18. Scherle PA, Jones EA, Favata MF, Daulerio AJ, Covington MB, Nurnberg SA, Magolda RL, Trzaskos JM: Inhibition of MAP kinase kinase prevents cytokine and prostaglandin E2 production in lipopolysaccharide-stimulated monocytes. J Immunol 161:5681-5686, 1998 
    19. Chandel NS, Trzyna WC, McClintock DS, Schumacker PT: Role of oxidants in NF-kappa B activation and TNF- alpha gene transcription induced by hypoxia and endotoxin. J Immunol 165:1013-1021, 2000 
    20. Karin M: Signal transduction from cell surface to nucleus in development and disease. FASEB J 6:2581-2590, 1992 
    21. Lahti A, Lahde M, Kankaanranta H, Moilanen E: Inhibition of extracellular signal-regulated kinase suppresses endotoxin-induced nitric oxide synthesis in mouse macrophages and in human colon epithelial cells. J Pharmacol Exp Ther 294:1188-1194, 2000 
    22. Kim SH, Sharma RP: Cytotoxicity of inorganic mercury in murine T and B lymphoma cell lines: involvement of reactive oxygen species, Ca (2+) homeostasis, and cytokine gene expression. Toxicol In Vitto 17:385-395, 2003 
    23. Ueda S, Masutani H, Nakamura H, Tanaka T, Ueno M, Yodoi J: Redox control of cell death. Antioxid Redox Signal 4:405-414, 2002 
    24. Wang SW, Pawlowski J, Wathen ST, Kinney SD, Lichenstein HS, Manthey CL: Cytokine mRNA decay is accelerated by an inhibitor of p38-mitogen-activated protein kinase. Inflamm Res 48:533-538, 1999 
    25. Monier RM, Orman KL, Meals EA, English BK: Differential effects of p38- and extracellular signal-regulated kinase mitogen-activated protein kinase inhibitors on inducible nitric oxide synthase and tumor necrosis factor production in murine macrophages stimulated with Streptococcus pneumoniae. J Infect Dis 185:921-926, 2002 
    26. Lahti A, Lahde M, Kankaanranta H, Moilanen E: Inhibition of extracellular signal-regulated kinase suppresses endotoxin-induced nitric oxide synthesis in mouse macrophages and in human colon epithelial cells. J Pharmacol Exp Ther 294:1188-1194, 2000 
    27. Tsukamoto H. Iron regulation of hepatic macrophage TNF-alpha expression. Free Radic Biol Med 32:309-313, 2002 
    28. Chan ED, Riches DW: IFN-gamma+LPS induction of iNOS is modulated by ERK, JNK/SAPK, and p38 (mapk) in a mouse macrophage cell line. Am J Physiol Cell Physiol 280:C441-C450, 2001 
    29. Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC: CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249:1431-1433,1990 
    30. Feng GJ, Goodridge HS, Harnett MM, Wei XQ, Nikolaev AV, Higson AP, Liew FY: Extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases differentially regulate the lipopolysaccharide-mediated induction of inducible nitric oxide synthase and IL-12 in macrophages: Leishmania phosphoglycans subvert macrophage IL-12 production by targeting ERK MAP kinase. J Immunol 163:6403-6412, 1999 
    31. Sharma RP, Bhandari N, Tsunoda M, Riley RT, Voss KA: Fumonisin hepatotoxicity is reduced in mice carrying the human tumour necrosis factor alpha transgene. Arch Toxicol 74:238-248, 2000 
    32. Ajizian SJ, English BK, Meals EA: Specific inhibitors of p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways block inducible nitric oxide synthase and tumor necrosis factor accumulation in murine macrophages stimulated with lipopolysaccharide and interferongamma. J Infect Dis 179:939-944, 1999 

 저자의 다른 논문

  • Choi, Cheol-Hee (14)

    1. 1991 "Forskolin의 흰쥐적출관류부신으로 부터 Ach, Excess $K^+$, DMPP, McN-A-343에 의한 Catecholamine 분비효과의 증강작용" The Korean journal of pharmacology : official journal of the Society of Pharmacology, Republic of Korea 27 (2): 167~181    
    2. 1992 "횐쥐 부신에서 Opioid가 니코틴 수용체를 통한 카테콜아민 분비작용에 미치는 영향" The Korean journal of pharmacology : official journal of the Society of Pharmacology, Republic of Korea 28 (2): 181~190    
    3. 1994 "흰쥐 관류부신에서 Pentazocine의 카테콜아민 분비작용의 기전" The Korean journal of pharmacology : official journal of the Society of Pharmacology, Republic of Korea 30 (3): 299~311    
    4. 1996 "Hydrocortisone이 적출 흰쥐 부신에서 Histamine의 카테콜아민 분비작용에 미치는 영향" The Korean journal of pharmacology : official journal of the Society of Pharmacology, Republic of Korea 32 (1): 83~91    
    5. 1998 "Mechanism of Vasoactive Intestinal Polypeptide-Induced Catecholamine Secretion from the Rat Adrenal Medulla" The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 2 (4): 443~454    
    6. 2000 "Influence of Staurosporine on Catecholamine Release Evoked by Cholinergic Stimulation and Membrane Depolarization from the Rat Adrenal Gland" The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 4 (2): 149~158    
    7. 2001 "Paraquat에 의한 생쥐 폐의 Superoxide Dismutases와 Metallothionein의 유도능과 노화와의 관계" 결핵 및 호흡기 질환 = Tuberculosis and respiratory diseases 50 (5): 579~590    
    8. 2003 "말초혈액 내 림프구의 방사선에 의한 아포프토시스" 대한방사선종양학회지 = The Journal of the Korean soceity for therapeutic radiology and oncology 21 (1): 75~81    
    9. 2004 "비장과 흉선의 림프세포와 LPS에 의해 유도된 사이토카인의 발현에 대한 수은의 영향" 약학회지 = Yakhak hoeji 48 (4): 241~246    
    10. 2004 "Differential Alterations of Endotoxin-induced Cytokine Expression and Mitogen-activated Protein Kinase Activation by Mercury in Mouse Kidney" Journal of toxicology and public health : an official journal of the Korean Society of Toxicology 20 (3): 233~239    
  • Kim, Sang-Hyun (11)

 활용도 분석

  • 상세보기

    amChart 영역
  • 원문보기

    amChart 영역

원문보기

무료다운로드
유료다운로드

유료 다운로드의 경우 해당 사이트의 정책에 따라 신규 회원가입, 로그인, 유료 구매 등이 필요할 수 있습니다. 해당 사이트에서 발생하는 귀하의 모든 정보활동은 NDSL의 서비스 정책과 무관합니다.

원문복사신청을 하시면, 일부 해외 인쇄학술지의 경우 외국학술지지원센터(FRIC)에서
무료 원문복사 서비스를 제공합니다.

NDSL에서는 해당 원문을 복사서비스하고 있습니다. 위의 원문복사신청 또는 장바구니 담기를 통하여 원문복사서비스 이용이 가능합니다.

이 논문과 함께 출판된 논문 + 더보기