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Intravenous immunoglobulin inhibits NF-κB activation and affects Fcγ receptor expression in monocytes/macrophages

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Abstract

High-dose intravenous immunoglobulin (IVIG) therapy is well established as a standard therapy for Kawasaki disease (KD) that reduces the risk of developing coronary artery aneurysms. Activation of monocytes/macrophages and tumor necrosis factor-α (TNF-α) activity are responsible for severe vascular injury in acute KD. We examined whether or not IVIG inhibits TNF-α-induced activation of transcription factor NF-κB, a factor that is essential for the expression of proinflammatory cytokines, in human monocytic U-937 cells. The inhibitory effect of IVIG on NF-κB activation induced by TNF-α was evaluated by Western blotting and flow cytometry. In addition, we examined the effect of IVIG on the expression of FcγIII (CD16) and FcγRIIb (CD32b) in U-937 cells and peripheral blood CD14+ monocytes/macrophages by flow cytometry. Western blotting demonstrated that IVIG inhibits NF-κB activation in U-937 cells, and flow cytometry that IVIG inhibits NF-κB activation in U-937 cells in a dose-related manner. Western blotting of cytoplasmic extracts of U-937 cells revealed that IVIG inhibited degradation of the IκBα protein. Moreover, flow cytometry demonstrated that IVIG decreased the expression of FcγRIII in U-937 cells and peripheral blood CD14+ monocytes/macrophages. However, Western blotting revealed that IVIG did not affect the quantity of FcγRIII protein, and PCR that IVIG did not affect the quantity of FcγRIII mRNA in the cells. These findings suggest that IVIG inhibits TNF-α-induced NF-κB activation in monocytes/macrophages, and blocks FcγRIII on the membranes of monocytes/macrophages.

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References

  • Andersson J, Skansén-Saphir U, Sparrelid E, Andersson U (1996) Intravenous immune globulin affects cytokine production in T lymphocytes and monocytes/macrophages. Clin Exp Immunol 104 [Suppl 1]:10–20

    Google Scholar 

  • Andersson JP, Andersson UG (1990) Human intravenous immunoglobulin modulates monokine production in vitro. Immunology 71:372–376

    CAS  PubMed  Google Scholar 

  • Ariga S, Koga M, Takahashi M, Ishihara T, Matsubara T, Furukawa S (2001) Maturation of macrophages from peripheral blood monocytes in Kawasaki disease: immunocytochemical and immunoelectron macroscopic study. Pathol Int 51:257–263

    Article  CAS  PubMed  Google Scholar 

  • Baeuerle PA, Henkel T (1994) Function and activation of NF-κB in the immune system. Annu Rev Immunol 12:141–179

    CAS  PubMed  Google Scholar 

  • Baldwin AS Jr (1996) The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol 14:649–683

    CAS  PubMed  Google Scholar 

  • Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U (1995) Control of IκB-α proteolysis by site-specific, signal-induced phosphorylation. Science 267:1485–1488

    CAS  PubMed  Google Scholar 

  • Chen CC, Rosenbloom CL, Anderson DC, Manning AM (1995) Selective inhibition of E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 expression by inhibitors of IκB-α phosphorylation. J Immunol 155:3538–3545

    CAS  PubMed  Google Scholar 

  • Collart MA, Baeuerle P, Vassalli P (1990) Regulation of tumor necrosis factor alpha transcription in macrophages: involvement of four κB-like motifs and of constitutive and inducible forms of NF-κB. Mol Cell Biol 10:1498–1506

    CAS  PubMed  Google Scholar 

  • Fujiwara H, Hamashima Y (1978) Pathology of the heart in Kawasaki disease. Pediatrics 61:100–107

    CAS  PubMed  Google Scholar 

  • Furukawa S, Matsubara T, Jujoh K, Yone K, Sugawara T, Sasai K, Kato H, Yabuta K (1988) Peripheral blood monocyte/macrophages and serum tumor necrosis factor in Kawasaki disease. Clin Immunol Immunopathol 48:247–251

    CAS  PubMed  Google Scholar 

  • Furukawa S, Matsubara T, Jujoh K, Sasai K, Nakachi S, Sugawara T, Yabuta K, Kato H (1990) Reduction of peripheral blood macrophages/monocytes in Kawasaki disease by intravenous gammaglobulin. Eur J Pediatr 150:43–47

    CAS  PubMed  Google Scholar 

  • Furukawa S, Imai K, Matsubara T, Yone K, Yachi A, Okumura K, Yabuta K (1992a) Increased levels of circulating intercellular adhesion molecule 1 in Kawasaki disease. Arthritis Rheum 35:672–677

    CAS  PubMed  Google Scholar 

  • Furukawa S, Matsubara T, Yone K, Hirano Y, Okumura K, Yabuta K (1992b) Kawasaki disease differs from anaphylactoid purpura and measles with regard to tumour necrosis factor-α and interleukin 6 in serum. Eur J Pediatr 151:44–47

    CAS  PubMed  Google Scholar 

  • Furukawa S, Matsubara T, Yabuta K (1992c) Mononuclear cell subsets and coronary artery lesions in Kawasaki disease. Arch Dis Child 67:706–708

    CAS  PubMed  Google Scholar 

  • Furukawa S, Matsubara T, Umezawa Y, Okumura K, Yabuta K (1994) Serum levels of p60 soluble tumor necrosis factor receptor during acute Kawasaki disease. J Pediatr 124:721–725

    CAS  PubMed  Google Scholar 

  • Furusho K, Kamiya T, Nakano H, Kiyosawa N, Shinomiya K, Hayashidera T, Tamura T, Hirose O, Manabe Y, Yokoyama T, Kawarano M, Baba K, Baba K, Mori C (1984) High-dose intravenous gammaglobulin for Kawasaki disease. Lancet 2:1055–1058

    Article  CAS  PubMed  Google Scholar 

  • Grimm S, Baeuerle PA (1993) The inducible transcription factor NF-κB: structure-function relationship of its protein subunits. Biochem J 290:297–308

    CAS  PubMed  Google Scholar 

  • Henkel T, Machleidt T, Alkalay I, Krönke M, Ben-Neriah Y, Baeuerle PA (1993) Rapid proteolysis of IκB-α is necessary for activation of transcriptional factor NF-κB. Nature 365:182–185

    CAS  PubMed  Google Scholar 

  • Hiscott J, Marois J, Garoufalis J, D’Addario M, Roulston A, Kwan I, Pepin N, Lacoste J, Nguyen H, Bensi G, Fenton M (1993) Characterization of a functional NF-κB site in the human interleukin 1β promotor: evidence for a positive autoregulatory loop. Mol Cell Biol 13:6231–6240

    CAS  PubMed  Google Scholar 

  • Ichiyama T, Nishikawa M, Yoshitomi T, Hasegawa S, Matsubara T, Hayashi T, Furukawa S (2001a) Clarithromycin inhibits NF-κB activation in human peripheral blood mononuclear cells and pulmonary epithelial cells. Antimicrob Agents Chemother 45:44–47

    Article  CAS  PubMed  Google Scholar 

  • Ichiyama T, Yoshitomi T, Nishikawa M, Fujiwara M, Matsubara T, Hayashi T, Furukawa S (2001b) NF-κB activation in peripheral blood monocytes/macrophages and T cells during acute Kawasaki disease. Clin Immunol 99:373–377

    Article  CAS  PubMed  Google Scholar 

  • Ichiyama T, Ueno Y, Isumi H, Niimi A, Matsubara T, Furukawa S (2004) An immunoglobulin agent (IVIG) inhibits NF-κB activation in cultured endothelial cells of coronary artery in vitro. Inflamm Res (in press)

  • Katayama K, Matsubara T, Fujiwara M, Koga M, Furukawa S (2000) CD14+CD16+ monocyte subpopulation in Kawasaki disease. Clin Exp Immunol 121:566–570

    Article  CAS  PubMed  Google Scholar 

  • Kato H, Sugimura T, Akagi T, Sato N, Hashino K, Maeno Y, Kazue T, Eto G, Yamakawa R (1996) Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients. Circulation 94:1379–1385

    CAS  PubMed  Google Scholar 

  • Kawasaki T, Kosaki F, Ogawa S, Shigemitsu I, Yanagawa H (1974) A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics 54:271–276

    CAS  PubMed  Google Scholar 

  • Koga M, Ishihara T, Takahashi M, Umezawa Y, Furukawa S (1998) Activation of peripheral blood monocytes and macrophages in Kawasaki disease: ultrastructural and immunocytochemical investigation. Pathol Int 48:512–517

    CAS  PubMed  Google Scholar 

  • Kumar A, Haque J, Lacoste J, Hiscott J, Williams BR (1994) Double-stranded RNA-dependent protein kinase activates transcription factor NF-κB by phosphorylating IκB. Proc Natl Acad Sci USA 91:6288–6292

    CAS  PubMed  Google Scholar 

  • Kunsch C, Lang RK, Rosen CA, Shannon MF (1994) Synergistic transcriptional activation of the IL-8 gene by NF-κB p65 (RelA) and NF-IL-6. J Immunol 153:153–164

    CAS  PubMed  Google Scholar 

  • Lang GA, Silverman ED, Laxer RM, Lau AS (1989) Spontaneous tumor necrosis factor production in Kawasaki disease. Lancet 2:1298–1302

    CAS  PubMed  Google Scholar 

  • Leung DY, Burns JC, Newburger JW, Geha RS (1987) Reversal of lymphocyte activation in vivo in the Kawasaki syndrome by intravenous gammaglobulin. J Clin Invest 79:468–472

    CAS  PubMed  Google Scholar 

  • Leung DYM, Cotran RS, Kurt-Johnes E, Burns JC, Newburger JW, Pober JS (1989) Endothelial cell activation and high interleukin-1 secretion in the pathogenesis of acute Kawasaki disease. J Pediatr 115:939–943

    PubMed  Google Scholar 

  • Libermann TA, Baltimore D (1990) Activation of interleukin-6 gene expression through the NF-κB transcription factor. Mol Cell Biol 10:2327–2334

    CAS  PubMed  Google Scholar 

  • Lin CY, Lin CC, Hwang B, Chiang B (1992) Serial changes of serum interleukin-6, interleukin-8, and tumor necrosis factor α among patients with Kawasaki disease. J Pediatr 121:924–926

    CAS  PubMed  Google Scholar 

  • Lin SY, Kinet JP (2001) Giving inhibitory receptors a boost. Science 291:445–446

    Article  CAS  PubMed  Google Scholar 

  • Matsusaka T, Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishimoto T, Akira S (1993) Transcription factors NF-IL6 and NF-κB synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc Natl Acad Sci USA 90:10193–10197

    CAS  PubMed  Google Scholar 

  • Maury CPJ, Salo E, Pelkonen P (1988) Circulating interleukin-1β in patients with Kawasaki disease. N Engl J Med 319:1670–1671

    CAS  PubMed  Google Scholar 

  • Maury CPJ, Salo E, Pelkonen P (1989) Elevated circulating tumor necrosis factor-α in patients with Kawasaki disease. J Lab Clin Med 113:651–654

    CAS  PubMed  Google Scholar 

  • Newburger JW, Takahashi M, Burns JC, Beiser AS, Chung KJ, Duffy CE, Glode MP, Mason WH, Reddy V, Sanders SP, Shulman ST, Wiggins JW, Hicks RV, Fulton DR, Lewis AB, Leung DYM, Colton T, Rosen FS, Melish ME (1986) The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 315:341–347

    CAS  PubMed  Google Scholar 

  • Newburger JW, Takahashi M, Beiser AS, Burns JC, Bastian J, Chung KJ, Colan SD, Duffy CE, Fulton DR, Glode MP, Mason WH, Meissner HC, Rowley AH, Shulman ST, Reddy V, Sundel RP, Wiggins JW, Colton T, Melish ME, Rosen FS (1991) A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med 324:1633–1639

    PubMed  Google Scholar 

  • Pyatt DW, Stillman WS, Yang Y, Gross S, Zheng JH, Irons RD (1999) An essential role for NF-κB in human CD34+ bone marrow cell survival. Blood 93:3302–3308

    CAS  PubMed  Google Scholar 

  • Samuelsson A, Towers TL, Ravetch JV (2001) Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291:484–486

    Article  CAS  PubMed  Google Scholar 

  • Sugawara T, Hattori S, Hirose S, Furukawa S, Yabuta K, Shirai T (1987) Immunopathology of the skin lesions of Kawasaki disease. In: Schulman ST (ed) Kawasaki disease. Liss, New York, pp 185–192

  • Terai M, Kohno Y, Namba M, Umemiya T, Miwa K, Nakajima H, Mikata A (1990) Class II major histocompatibility antigen expression on coronary arterial endothelium in a patient with Kawasaki disease. Hum Pathol 21:231–234

    CAS  PubMed  Google Scholar 

  • Toungouz M, Denys CH, De Groote D, Dupont E (1995) In vitro inhibition of tumour necrosis factor-α and interleukin-6 production by intravenous immunoglobulins. Br J Haematol 89:698–703

    CAS  PubMed  Google Scholar 

  • Tridandapani S, Siefker K, Teillaud JL, Carter JE, Wewers MD, Anderson CL (2002) Regulated expression and inhibitory function of FcγRIIb in human monocytic cells. J Biol Chem 277:5082–5089

    Article  CAS  PubMed  Google Scholar 

  • Ueda A, Ishigatsubo Y, Okubo T, Yoshimura T (1997) Transcriptional regulation of the human monocyte chemoattractant protein-1 gene. Cooperation of two NF-κB sites and NF-κB/Rel subunit specificity. J Biol Chem 272:31092–31099

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, Yamaguchi University School of Medicine, 1–1-1 Minamikogushi, 755–8505, Ube, Yamaguchi, Japan

    Takashi Ichiyama, Yoshiko Ueno, Masanari Hasegawa, Tomoyo Matsubara & Susumu Furukawa

  2. Bayer Yakuhin Ltd., 5–36, Miyahara 3-chome, 532–8577, Yodogawa-ku, Osaka, Japan

    Akihiro Niimi

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  1. Takashi Ichiyama
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  2. Yoshiko Ueno
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  3. Masanari Hasegawa
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  4. Akihiro Niimi
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  5. Tomoyo Matsubara
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  6. Susumu Furukawa
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Correspondence to Takashi Ichiyama.

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Ichiyama, T., Ueno, Y., Hasegawa, M. et al. Intravenous immunoglobulin inhibits NF-κB activation and affects Fcγ receptor expression in monocytes/macrophages. Naunyn-Schmiedeberg's Arch Pharmacol 369, 428–433 (2004). https://doi.org/10.1007/s00210-004-0877-x

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