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References

  1. Bertolini A, Ottani A, Sandrini M. 2001. Dual acting antiinflammatory drugs: a reappraisal. Pharmacol. Res. 44: 437-450.
    Pubmed CrossRef
  2. Broad A, Jones DE, Kirby JA. 2006. Toll-like receptor (TLR) response tolerance: a key physiological “damage limitation” effect and an important potential opportunity for therapy. Curr. Med. Chem. 13: 2487-2502.
    Pubmed CrossRef
  3. Brockman JA, Scherer DC, McKinsey TA, Hall SM, Qi X, Lee WY, Ballard DW. 1995. Coupling of a signal response domain in I kappa B alpha to multiple pathways for NFkappa B activation. Mol. Cell. Biol. 15: 2809-2818.
    Pubmed PMC CrossRef
  4. Carter AB, Knudtson KL, Monick MM, Hunninghake GW. 1999. The p38 mitogen-activated protein kinase is required for NF-kappaB-dependent gene expression. The role of TATA-binding protein (TBP). J. Biol. Chem. 274: 30858-30863.
    Pubmed CrossRef
  5. Chan ED, Riches DW. 2001. IFN-gamma + LPS induction of iNOS is modulated b y ERK, JNK/SAPK, and p 38(mapk) in a mouse macrophage cell line. Am. J. Physiol. Cell Physiol. 280: C441-C450.
    Pubmed
  6. Chen CC, Wang JK. 1999. p38 but not p44/42 mitogenactivated protein kinase is required for nitric oxide synthase induction mediated by lipopolysaccharide in RAW 264.7 macrophages. Mol. Pharmacol. 55: 481-488.
    Pubmed
  7. Geng Y, Zhang B, Lotz M. 1993. Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes. J. Immunol. 151: 66926700.
  8. Ghosh S, Karin M. 2002. Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl): S81-S96.
    CrossRef
  9. Guha M, Mackman N. 2001. LPS induction of gene expression in human monocytes. Cell. Signal. 13: 85-94.
    CrossRef
  10. Kanterman J, Sade-Feldman M, Baniyash M. 2012. New insights into chronic inflammation-induced immunosuppression. Seminars Cancer Biol. 22: 307-318.
    Pubmed CrossRef
  11. Karin M. 1999. The beginning of the end: IkappaB kinase (IKK) and NF-kappaB activation. J. Biol. Chem. 274: 27339-27342.
    Pubmed CrossRef
  12. Klemm S, Ruland J. 2006. Inflammatory signal transduction from the Fc epsilon RI to NF-kappa B. Immunobiology 211:815-820.
    Pubmed CrossRef
  13. Lawrence T. 2009. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harbor Perspect. Biol. 1: a001651.
    Pubmed PMC CrossRef
  14. Lee FS, Peters RT, Dang LC, Maniatis T. 1998. MEKK1 activates both IkappaB kinase alpha and IkappaB kinasebeta. Proc. Natl. Acad. Sci. USA 95: 9319-9324.
    Pubmed PMC CrossRef
  15. Liu SF, Malik AB. 2006. NF-kappa B activation as a pathological mechanism of septic shock and inflammation. Am. J. Physiol. Lung Cell. Mol. Physiol. 290: L622-L645.
    Pubmed CrossRef
  16. Lowenstein CJ, Alley EW, Raval P, Snowman AM, Snyder SH, Russell SW, Murphy WJ. 1993. Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc. Natl. Acad. Sci. USA 90: 9730-9734.
    Pubmed PMC CrossRef
  17. MacMicking J, Xie QW, Nathan C. 1997. Nitric oxide and macrophage function. Annu. Rev. Immunol. 15: 323-350.
    Pubmed CrossRef
  18. Marks-Konczalik J, Chu SC, Moss J. 1998. Cytokinemediated transcriptional induction of the human inducible nitric oxide synthase gene requires both activator protein 1 and nuclear factor kappaB-binding sites. J. Biol. Chem. 273:22201-22208.
    Pubmed CrossRef
  19. Matsushima A, Kaisho T, Rennert PD, Nakano H, Kurosawa K, Uchida D, et al. 2001. Essential role of nuclear factor (NF)-kappaB-inducing kinase and inhibitor of kappaB (IkappaB) kinase alpha in NF-kappaB activation through lymphotoxin beta receptor, but not through tumor necrosis factor receptor I. J. Exp. Med. 193: 631-636.
    Pubmed PMC CrossRef
  20. Michel T, Feron O. 1997. Nitric oxide synthases: which, where, how, and why? J. Clin. Invest. 100: 2146-2152.
    Pubmed PMC CrossRef
  21. Miller SI, Ernst RK, Bader MW. 2005. LPS, TLR4 and infectious disease diversity. Nature Rev. Microbiol. 3: 36-46.
    Pubmed CrossRef
  22. Nakano H, Shindo M, Sakon S, Nishinaka S, Mihara M, Yagita H, Okumura K. 1998. Differential regulation of IkappaB kinase alpha and beta by two upstream kinases, NF-kappaB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1. Proc. Natl. Acad. Sci. USA 95:3537-3542.
    Pubmed PMC CrossRef
  23. Netea MG, van der Meer JW, van Deuren M, Kullberg BJ. 2003. Proinflammatory cytokines and sepsis syndrome: not enough, or too much of a good thing? Trends Immunol. 24:254-258.
    CrossRef
  24. Perkins ND. 2000. The Rel/NF-kappa B family: friend and foe. Biochem. Sci. 25: 434-440.
    CrossRef
  25. Raetz CR, Whitfield C. 2002. Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 71: 635-700.
    Pubmed PMC CrossRef
  26. Shin HM, Kim MH, Kim BH, Jung SH, Kim YS, Park HJ, et al. 2004. Inhibitory action of novel aromatic diamine compound on lipopolysaccharide-induced nuclear translocation of NFkappaB without affecting IkappaB degradation. FEBS Lett. 571: 50-54.
    Pubmed CrossRef
  27. Stancovski I, Baltimore D. 1997. NF-kappaB activation: the I kappaB kinase revealed? Cell 91: 299-302.
    CrossRef
  28. Takeda K, Akira S. 2004. TLR signaling pathways. Seminars Immunol. 16: 3-9.
    Pubmed CrossRef
  29. Wu JT, Kral JG. 2005. The NF-kappaB/IkappaB signaling system: a molecular target in breast cancer therapy. J. Surg. Res. 123: 158-169.
    Pubmed CrossRef
  30. Xie QW, Kashiwabara Y, Nathan C. 1994. Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J. Biol. Chem. 269: 4705-4708.
    Pubmed
  31. Xie QW, Whisnant R, Nathan C. 1993. Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J. Exp. Med. 177: 1779-1784.
    Pubmed CrossRef
  32. Zamora R, Vodovotz Y, Billiar TR. 2000. Inducible nitric oxide synthase and inflammatory diseases. Mol. Med. 6: 347-373.
    Pubmed PMC
  33. Zandi E, Chen Y, Karin M. 1998. Direct phosphorylation of IkappaB by IKKα and IKKβ: discrimination between free and NF-kappaB-bound substrate. Science 281: 1360-1363.
    Pubmed CrossRef
  34. Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M. 1997. The IkappaB kinase complex (IKK) contains two kinase subunits, IKKα and IKKβ, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 91: 243-252.
    CrossRef
  35. Zhang W, Liu HT. 2002. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 12: 9-18.
    Pubmed CrossRef

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Article

Research article

J. Microbiol. Biotechnol. 2015; 25(7): 1047-1055

Published online July 28, 2015 https://doi.org/10.4014/jmb.1504.04027

Copyright © The Korean Society for Microbiology and Biotechnology.

A Novel Synthetic Compound, YH-1118, Inhibited LPS-Induced Inflammatory Response by Suppressing IκB Kinase/NF-κB Pathway in Raw 264.7 Cells

Chang Hyun Yun 1, Eun Jung Jang 1, Soon Cheon Kwon 1, Mee-Young Lee 2, Sangku Lee 2, Sei-Ryang Oh 2, Hyeong-Kyu Lee 2, Kyung-Seop Ahn 2 and Ho-Jae Lee 1*

1Laboratory of Chemoprevention, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Republic of Korea, 2Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk 363-883, Republic of Korea

Received: April 13, 2015; Accepted: April 22, 2015

Abstract

For the search of a potent first-in-class compound to inactivate macrophages responsible for
inflammatory responses, in the present study, we investigated the anti-inflammatory effects of
YH-1118, a novel synthetic compound, in a lipopolysaccharide (LPS)-stimulated mouse
macrophage cell line, Raw 264.7. YH-1118 inhibited LPS-induced nitric oxide (NO) production
and inducible NO synthase (iNOS) expression at both the protein and mRNA levels. The
suppression of LPS-induced iNOS expression by YH-1118 was mediated via nuclear factor
kappa B (NF-κB), but not activator protein-1 (AP-1) transcription factor. This was supported
by the finding that YH-1118 attenuated the phosphorylation of inhibitor of κBα (IκBα) and
nuclear translocation and DNA binding activity of NF-κB. Through the mechanisms that YH-
1118 inhibited the activation of IκB kinases (IKKs), upstream activators of NF-κB, or p38
MAPK, YH-1118 significantly suppressed LPS-induced production of pro-inflammatory
cytokines, tumor necrosis factor-α, interleukin-1β (IL-1β), and IL-6 (p < 0.05). In conclusion,
our results suggest that YH-1118 inhibits LPS-induced inflammatory responses by blocking
IKK and NF-κB activation in macrophages, and may be a therapeutic candidate for the
treatment of various inflammatory diseases.

Keywords: YH-1118, iNOS, NF-κB, macrophages, inflammation

References

  1. Bertolini A, Ottani A, Sandrini M. 2001. Dual acting antiinflammatory drugs: a reappraisal. Pharmacol. Res. 44: 437-450.
    Pubmed CrossRef
  2. Broad A, Jones DE, Kirby JA. 2006. Toll-like receptor (TLR) response tolerance: a key physiological “damage limitation” effect and an important potential opportunity for therapy. Curr. Med. Chem. 13: 2487-2502.
    Pubmed CrossRef
  3. Brockman JA, Scherer DC, McKinsey TA, Hall SM, Qi X, Lee WY, Ballard DW. 1995. Coupling of a signal response domain in I kappa B alpha to multiple pathways for NFkappa B activation. Mol. Cell. Biol. 15: 2809-2818.
    Pubmed KoreaMed CrossRef
  4. Carter AB, Knudtson KL, Monick MM, Hunninghake GW. 1999. The p38 mitogen-activated protein kinase is required for NF-kappaB-dependent gene expression. The role of TATA-binding protein (TBP). J. Biol. Chem. 274: 30858-30863.
    Pubmed CrossRef
  5. Chan ED, Riches DW. 2001. IFN-gamma + LPS induction of iNOS is modulated b y ERK, JNK/SAPK, and p 38(mapk) in a mouse macrophage cell line. Am. J. Physiol. Cell Physiol. 280: C441-C450.
    Pubmed
  6. Chen CC, Wang JK. 1999. p38 but not p44/42 mitogenactivated protein kinase is required for nitric oxide synthase induction mediated by lipopolysaccharide in RAW 264.7 macrophages. Mol. Pharmacol. 55: 481-488.
    Pubmed
  7. Geng Y, Zhang B, Lotz M. 1993. Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes. J. Immunol. 151: 66926700.
  8. Ghosh S, Karin M. 2002. Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl): S81-S96.
    CrossRef
  9. Guha M, Mackman N. 2001. LPS induction of gene expression in human monocytes. Cell. Signal. 13: 85-94.
    CrossRef
  10. Kanterman J, Sade-Feldman M, Baniyash M. 2012. New insights into chronic inflammation-induced immunosuppression. Seminars Cancer Biol. 22: 307-318.
    Pubmed CrossRef
  11. Karin M. 1999. The beginning of the end: IkappaB kinase (IKK) and NF-kappaB activation. J. Biol. Chem. 274: 27339-27342.
    Pubmed CrossRef
  12. Klemm S, Ruland J. 2006. Inflammatory signal transduction from the Fc epsilon RI to NF-kappa B. Immunobiology 211:815-820.
    Pubmed CrossRef
  13. Lawrence T. 2009. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harbor Perspect. Biol. 1: a001651.
    Pubmed KoreaMed CrossRef
  14. Lee FS, Peters RT, Dang LC, Maniatis T. 1998. MEKK1 activates both IkappaB kinase alpha and IkappaB kinasebeta. Proc. Natl. Acad. Sci. USA 95: 9319-9324.
    Pubmed KoreaMed CrossRef
  15. Liu SF, Malik AB. 2006. NF-kappa B activation as a pathological mechanism of septic shock and inflammation. Am. J. Physiol. Lung Cell. Mol. Physiol. 290: L622-L645.
    Pubmed CrossRef
  16. Lowenstein CJ, Alley EW, Raval P, Snowman AM, Snyder SH, Russell SW, Murphy WJ. 1993. Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc. Natl. Acad. Sci. USA 90: 9730-9734.
    Pubmed KoreaMed CrossRef
  17. MacMicking J, Xie QW, Nathan C. 1997. Nitric oxide and macrophage function. Annu. Rev. Immunol. 15: 323-350.
    Pubmed CrossRef
  18. Marks-Konczalik J, Chu SC, Moss J. 1998. Cytokinemediated transcriptional induction of the human inducible nitric oxide synthase gene requires both activator protein 1 and nuclear factor kappaB-binding sites. J. Biol. Chem. 273:22201-22208.
    Pubmed CrossRef
  19. Matsushima A, Kaisho T, Rennert PD, Nakano H, Kurosawa K, Uchida D, et al. 2001. Essential role of nuclear factor (NF)-kappaB-inducing kinase and inhibitor of kappaB (IkappaB) kinase alpha in NF-kappaB activation through lymphotoxin beta receptor, but not through tumor necrosis factor receptor I. J. Exp. Med. 193: 631-636.
    Pubmed KoreaMed CrossRef
  20. Michel T, Feron O. 1997. Nitric oxide synthases: which, where, how, and why? J. Clin. Invest. 100: 2146-2152.
    Pubmed KoreaMed CrossRef
  21. Miller SI, Ernst RK, Bader MW. 2005. LPS, TLR4 and infectious disease diversity. Nature Rev. Microbiol. 3: 36-46.
    Pubmed CrossRef
  22. Nakano H, Shindo M, Sakon S, Nishinaka S, Mihara M, Yagita H, Okumura K. 1998. Differential regulation of IkappaB kinase alpha and beta by two upstream kinases, NF-kappaB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1. Proc. Natl. Acad. Sci. USA 95:3537-3542.
    Pubmed KoreaMed CrossRef
  23. Netea MG, van der Meer JW, van Deuren M, Kullberg BJ. 2003. Proinflammatory cytokines and sepsis syndrome: not enough, or too much of a good thing? Trends Immunol. 24:254-258.
    CrossRef
  24. Perkins ND. 2000. The Rel/NF-kappa B family: friend and foe. Biochem. Sci. 25: 434-440.
    CrossRef
  25. Raetz CR, Whitfield C. 2002. Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 71: 635-700.
    Pubmed KoreaMed CrossRef
  26. Shin HM, Kim MH, Kim BH, Jung SH, Kim YS, Park HJ, et al. 2004. Inhibitory action of novel aromatic diamine compound on lipopolysaccharide-induced nuclear translocation of NFkappaB without affecting IkappaB degradation. FEBS Lett. 571: 50-54.
    Pubmed CrossRef
  27. Stancovski I, Baltimore D. 1997. NF-kappaB activation: the I kappaB kinase revealed? Cell 91: 299-302.
    CrossRef
  28. Takeda K, Akira S. 2004. TLR signaling pathways. Seminars Immunol. 16: 3-9.
    Pubmed CrossRef
  29. Wu JT, Kral JG. 2005. The NF-kappaB/IkappaB signaling system: a molecular target in breast cancer therapy. J. Surg. Res. 123: 158-169.
    Pubmed CrossRef
  30. Xie QW, Kashiwabara Y, Nathan C. 1994. Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J. Biol. Chem. 269: 4705-4708.
    Pubmed
  31. Xie QW, Whisnant R, Nathan C. 1993. Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J. Exp. Med. 177: 1779-1784.
    Pubmed CrossRef
  32. Zamora R, Vodovotz Y, Billiar TR. 2000. Inducible nitric oxide synthase and inflammatory diseases. Mol. Med. 6: 347-373.
    Pubmed KoreaMed
  33. Zandi E, Chen Y, Karin M. 1998. Direct phosphorylation of IkappaB by IKKα and IKKβ: discrimination between free and NF-kappaB-bound substrate. Science 281: 1360-1363.
    Pubmed CrossRef
  34. Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M. 1997. The IkappaB kinase complex (IKK) contains two kinase subunits, IKKα and IKKβ, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 91: 243-252.
    CrossRef
  35. Zhang W, Liu HT. 2002. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 12: 9-18.
    Pubmed CrossRef