Inflammation Research

, Volume 63, Issue 9, pp 711–718 | Cite as

Intravenous immunoglobulin preparation prevents the production of pro-inflammatory cytokines by modulating NFκB and MAPKs pathways in the human monocytic THP-1 cells stimulated with procalcitonin

  • Kazuki Murakami
  • Chiaki Suzuki
  • Akihiro Fujii
  • Fujio Kobayashi
  • Atsushi Nakano
  • Akihito Kamizono
Original Research Paper



In the previous investigations, we showed that intravenous immunoglobulin (IVIG) prevented cytokine release in procalcitonin (PCT)-stimulated monocytic cells. The aim of the present study was to investigate the underlying mechanisms of inhibition of IVIG on cytokine production in PCT-stimulated THP-1 cells.


THP-1 cells treated with phorbol myristate acetate were stimulated with PCT. The protein levels of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and high-mobility group box 1 (HMGB1)] in the culture supernatants were determined using enzyme-linked immunosorbent assay kits. The mRNA level of TNF-α was determined by reverse transcription-polymerase chain reaction. The phosphorylations of nuclear factor kappa B (NFκB) and the mitogen-activated protein kinases (MAPKs) were determined by Western blotting.


IVIG reduced mRNA expression and protein production of TNF-α in PCT-stimulated THP-1 cells. Not only IVIG but also both the Fc fragment and the F(ab’)2 fragment inhibited PCT-induced TNF-α, IL-6, and HMGB1 production. Furthermore, IVIG and its fragments suppressed PCT-induced phosphorylations of NFκB, p38 MAPK, and c-Jun N-terminal kinase.


Our results indicate that IVIG prevents PCT-induced cytokine production mediated by not only the Fab region but also the Fc region. The activity of IVIG and its fragments might be regulated by inhibiting NFκB and MAPKs pathways in THP-1 cells.


Intravenous immunoglobulin Fc fragment Procalcitonin THP-1 cells TNF-α NFκB 


  1. 1.
    Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet. 1993;341:515–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Schuetz P, Albrich W, Mueller B. Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, present and future. BMC Med. 2011;9:107.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Riedel S. Procalcitonin and the role of biomarkers in the diagnosis and management of sepsis. Diagn Microbiol Infect Dis. 2012;73:221–7.PubMedGoogle Scholar
  4. 4.
    Becker KL, Snider R, Nylen ES. Procalcitonin in sepsis and systemic inflammation: a harmful biomarker and a therapeutic target. Br J Pharmacol. 2010;159:253–64.PubMedCentralPubMedGoogle Scholar
  5. 5.
    Matwiyoff GN, Prahl JD, Miller RJ, Carmichael JJ, Amundson DE, Seda G, Daheshia M. Immune regulation of procalcitonin: a biomarker and mediator of infection. Inflamm Res. 2012;61:401–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Murakami K, Suzuki C, Fujii A, Imada T. Intravenous immunoglobulin prevents release of proinflammatory cytokines in human monocytic cells stimulated with procalcitonin. Inflamm Res. 2012;61:617–22.PubMedCrossRefGoogle Scholar
  7. 7.
    Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med. 2001;345:747–55.PubMedCrossRefGoogle Scholar
  8. 8.
    Negi VS, Elluru S, Sibéril S, Graff-Dubois S, Mouthon L, Kazatchkine MD, Lacroix-Desmazes S, Bayry J, Kaveri SV. Intravenous immunoglobulin: an update on the clinical use and mechanisms of action. J Clin Immunol. 2007;27:233–45.PubMedCrossRefGoogle Scholar
  9. 9.
    Andersson U, Björk L, Skansén-Saphir U, Andersson J. Pooled human IgG modulates cytokine production in lymphocytes and monocytes. Immunol Rev. 1994;139:21–42.PubMedCrossRefGoogle Scholar
  10. 10.
    Ulloa L, Tracey KJ. The “cytokine profile”: a code for sepsis. Trends Mol Med. 2005;11:56–63.PubMedCrossRefGoogle Scholar
  11. 11.
    Furukawa S, Matsubara T, Yone K, Hirano Y, Okumura K, Yabuta K. Kawasaki disease differs from anaphylactoid purpura and measles with regard to tumour necrosis factor-α and interleukin 6 in serum. Eur J Pediatr. 1992;151:44–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Lin CY, Lin CC, Hwang B, Chiang B. Serial changes of serum interleukin-6, interleukin-8, and tumor necrosis factor α among patients with Kawasaki disease. J Pediatr. 1992;121:924–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Maury CPJ, Salo E, Pelkonen P. Circulating interleukin-1β in patients with Kawasaki disease. N Engl J Med. 1988;319:1670–1.PubMedCrossRefGoogle Scholar
  14. 14.
    Shimozato T, Iwata M, Kawada H, Tamura N. Human immunoglobulin preparation for intravenous use induces elevation of cellular cyclic adenosine 3′:5′-monophosphate levels, resulting in suppression of tumour necrosis factor alpha and interleukin-1 production. Immunology. 1991;72:497–501.PubMedCentralPubMedGoogle Scholar
  15. 15.
    Toungouz M, Denys CH, de Groote D, Dupont E. In vitro inhibition of tumour necrosis factor-α and interleukin-6 production by intravenous immunoglobulins. Br J Haematol. 1995;89:698–703.PubMedCrossRefGoogle Scholar
  16. 16.
    Wu KH, Wu WM, Lu MY, Chiang BL. Inhibitory effect of pooled human immunoglobulin on cytokine production in peripheral blood mononuclear cells. Pediatr Allergy Immunol. 2006;17:60–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Murakami K, Suzuki C, Kobayashi F, Nakano A, Fujii A, Sakai K, Imada T. Intravenous immunoglobulin preparation attenuates LPS-induced production of pro-inflammatory cytokines in human monocytic cells by modulating TLR4-mediated signaling pathways. Naunyn-Schmiedebergs Arch Pharmacol. 2012;385:891–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Park EK, Jung HS, Yang HI, Yoo MC, Kim C, Kim KS. Optimized THP-1 differentiation is required for the detection of responses to weak stimuli. Inflamm Res. 2007;56:45–50.PubMedCrossRefGoogle Scholar
  19. 19.
    Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3:1101–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Ballow M. The IgG molecule as a biological immune response modifier: mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders. J Allergy Clin Immunol. 2011;127:315–23.PubMedCrossRefGoogle Scholar
  21. 21.
    Sharif O, Bolshakov VN, Raines S, Newham P, Perkins ND. Transcriptional profiling of the LPS induced NF-κB response in macrophages. BMC Immunol. 2007;8:1–17.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Fujii A, Kase Y, Suzuki C, Kamizono A, Imada T. An Fc gamma receptor-mediated upregulation of the production of interleukin 10 by intravenous immunoglobulin in bone-marrow-derived mouse dendritic cells stimulated with lipopolysaccharide in vitro. J Signal Transduct. 2013;2013:239320.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Crow AR, Song S, Semple JW, Freedman J, Lazarus AH. IVIg inhibits reticuloendothelial system function and ameliorates murine passive-immune thrombocytopenia independent of anti-idiotype reactivity. Br J Haematol. 2001;115:679–86.PubMedCrossRefGoogle Scholar
  24. 24.
    de Grandmont MJ, Racine C, Roy A, Lemieux R, Néron S. Intravenous immunoglobulins induce the in vitro differentiation of human B lymphocytes and the secretion of IgG. Blood. 2003;101:3065–73.PubMedCrossRefGoogle Scholar
  25. 25.
    Tha-In T, Metselaar HJ, Tilanus HW, Groothuismink ZM, Kuipers EJ, de Man RA, Kwekkeboom J. Intravenous immunoglobulins suppress T-cell priming by modulating the bidirectional interaction between dendritic cells and natural killer cells. Blood. 2007;110:3253–62.PubMedCrossRefGoogle Scholar
  26. 26.
    Cantin AM, Paquette B, Richter M, Larivée P. Albumin-mediated regulation of cellular glutathione and nuclear factor kappa B activation. Am J Respir Crit Care Med. 2000;162:1539–46.PubMedGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  • Kazuki Murakami
    • 1
  • Chiaki Suzuki
    • 1
  • Akihiro Fujii
    • 1
  • Fujio Kobayashi
    • 1
  • Atsushi Nakano
    • 1
  • Akihito Kamizono
    • 1
  1. 1.Central Research Laboratory, Research and Development DivisionJapan Blood Products OrganizationKobeJapan

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