Europe PMC

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy.

Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral blood mononuclear cells: priming for IL-12 and tumor necrosis factor alpha production.

Author information

Affiliations

  • 1. Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania 19104.
      Authors
    • D'Andrea A 1
    (1 author)

The Journal of Experimental Medicine, 01 Feb 1995, 181(2):537-546
https://doi.org/10.1084/jem.181.2.537 PMID: 7836910 PMCID: PMC2191875

This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC

Abstract 

The production of cytokines in monocytes/macrophages is regulated by several different cytokines that have activating or inhibitory effects. Interleukin (IL)-10, IL-4, IL-13, and transforming growth factor (TGF)-beta are usually considered to be the most important macrophage-deactivating factors, with inhibitory effects on cytokine production. Unlike IL-10 and TGF-beta, which appear to act as downmodulators of many phagocytic cell functions, the mode of action of IL-4 and IL-13 is more complex. Addition of IL-4 and IL-13 to peripheral blood mononuclear cell (PBMC) cultures inhibited production of IL-12, tumor necrosis factor (TNF)-alpha, IL-10, and IL-1 beta induced by lipopolysaccharide (LPS) or Staphylococcus aureus added simultaneously with the cytokines. However, pretreatment of PBMC with IL-4 or IL-13 for > or = 20 h enhanced the production of IL-12 and TNF-alpha in response to LPS or S. aureus several fold in these cells; this IL-4-induced priming for the two cytokines was inhibited by anti-IL-4 neutralizing antibodies. IL-4 priming also enhanced the accumulation of IL-12 and TNF-alpha mRNA induced by LPS and S. aureus. The enhanced accumulation of transcripts for the IL-12 p35 and p40 chains by IL-4 priming was reflected in enhanced secretion of both the IL-12 free p40 chain and the p70 heterodimer. These results suggest an unexpected complexity in the regulatory role of IL-4 and IL-13 in immune responses.

Free full text 

Logo of jexpmedLink to Publisher's site
J Exp Med. 1995 Feb 1; 181(2): 537–546.
PMCID: PMC2191875
PMID: 7836910

Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral blood mononuclear cells: priming for IL-12 and tumor necrosis factor alpha production

Copyright and License information Disclaimer

Abstract

The production of cytokines in monocytes/macrophages is regulated by several different cytokines that have activating or inhibitory effects. Interleukin (IL)-10, IL-4, IL-13, and transforming growth factor (TGF)- beta are usually considered to be the most important macrophage- deactivating factors, with inhibitory effects on cytokine production. Unlike IL-10 and TGF-beta, which appear to act as downmodulators of many phagocytic cell functions, the mode of action of IL-4 and IL-13 is more complex. Addition of IL-4 and IL-13 to peripheral blood mononuclear cell (PBMC) cultures inhibited production of IL-12, tumor necrosis factor (TNF)-alpha, IL-10, and IL-1 beta induced by lipopolysaccharide (LPS) or Staphylococcus aureus added simultaneously with the cytokines. However, pretreatment of PBMC with IL-4 or IL-13 for > or = 20 h enhanced the production of IL-12 and TNF-alpha in response to LPS or S. aureus several fold in these cells; this IL-4- induced priming for the two cytokines was inhibited by anti-IL-4 neutralizing antibodies. IL-4 priming also enhanced the accumulation of IL-12 and TNF-alpha mRNA induced by LPS and S. aureus. The enhanced accumulation of transcripts for the IL-12 p35 and p40 chains by IL-4 priming was reflected in enhanced secretion of both the IL-12 free p40 chain and the p70 heterodimer. These results suggest an unexpected complexity in the regulatory role of IL-4 and IL-13 in immune responses.

Full Text

The Full Text of this article is available as a PDF (1019K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, Loudon R, Sherman F, Perussia B, Trinchieri G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989 Sep 1;170(3):827–845. [Europe PMC free article] [Abstract] [Google Scholar]
  • D'Andrea A, Rengaraju M, Valiante NM, Chehimi J, Kubin M, Aste M, Chan SH, Kobayashi M, Young D, Nickbarg E, et al. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med. 1992 Nov 1;176(5):1387–1398. [Europe PMC free article] [Abstract] [Google Scholar]
  • D'Andrea A, Aste-Amezaga M, Valiante NM, Ma X, Kubin M, Trinchieri G. Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med. 1993 Sep 1;178(3):1041–1048. [Europe PMC free article] [Abstract] [Google Scholar]
  • Murphy EE, Terres G, Macatonia SE, Hsieh CS, Mattson J, Lanier L, Wysocka M, Trinchieri G, Murphy K, O'Garra A. B7 and interleukin 12 cooperate for proliferation and interferon gamma production by mouse T helper clones that are unresponsive to B7 costimulation. J Exp Med. 1994 Jul 1;180(1):223–231. [Europe PMC free article] [Abstract] [Google Scholar]
  • Kubin M, Kamoun M, Trinchieri G. Interleukin 12 synergizes with B7/CD28 interaction in inducing efficient proliferation and cytokine production of human T cells. J Exp Med. 1994 Jul 1;180(1):211–222. [Europe PMC free article] [Abstract] [Google Scholar]
  • Manetti R, Parronchi P, Giudizi MG, Piccinni MP, Maggi E, Trinchieri G, Romagnani S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 1993 Apr 1;177(4):1199–1204. [Europe PMC free article] [Abstract] [Google Scholar]
  • Hsieh CS, Macatonia SE, Tripp CS, Wolf SF, O'Garra A, Murphy KM. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. [Abstract] [Google Scholar]
  • Germann T, Gately MK, Schoenhaut DS, Lohoff M, Mattner F, Fischer S, Jin SC, Schmitt E, Rüde E. Interleukin-12/T cell stimulating factor, a cytokine with multiple effects on T helper type 1 (Th1) but not on Th2 cells. Eur J Immunol. 1993 Aug;23(8):1762–1770. [Abstract] [Google Scholar]
  • Wolf SF, Temple PA, Kobayashi M, Young D, Dicig M, Lowe L, Dzialo R, Fitz L, Ferenz C, Hewick RM, et al. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol. 1991 May 1;146(9):3074–3081. [Abstract] [Google Scholar]
  • Gubler U, Chua AO, Schoenhaut DS, Dwyer CM, McComas W, Motyka R, Nabavi N, Wolitzky AG, Quinn PM, Familletti PC, et al. Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4143–4147. [Europe PMC free article] [Abstract] [Google Scholar]
  • Stern AS, Podlaski FJ, Hulmes JD, Pan YC, Quinn PM, Wolitzky AG, Familletti PC, Stremlo DL, Truitt T, Chizzonite R, et al. Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6808–6812. [Europe PMC free article] [Abstract] [Google Scholar]
  • Nathan CF, Murray HW, Wiebe ME, Rubin BY. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med. 1983 Sep 1;158(3):670–689. [Europe PMC free article] [Abstract] [Google Scholar]
  • Kubin M, Chow JM, Trinchieri G. Differential regulation of interleukin-12 (IL-12), tumor necrosis factor alpha, and IL-1 beta production in human myeloid leukemia cell lines and peripheral blood mononuclear cells. Blood. 1994 Apr 1;83(7):1847–1855. [Abstract] [Google Scholar]
  • Bogdan C, Nathan C. Modulation of macrophage function by transforming growth factor beta, interleukin-4, and interleukin-10. Ann N Y Acad Sci. 1993 Jun 23;685:713–739. [Abstract] [Google Scholar]
  • Taga K, Mostowski H, Tosato G. Human interleukin-10 can directly inhibit T-cell growth. Blood. 1993 Jun 1;81(11):2964–2971. [Abstract] [Google Scholar]
  • de Waal Malefyt R, Yssel H, de Vries JE. Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol. 1993 Jun 1;150(11):4754–4765. [Abstract] [Google Scholar]
  • Hsu DH, Moore KW, Spits H. Differential effects of IL-4 and IL-10 on IL-2-induced IFN-gamma synthesis and lymphokine-activated killer activity. Int Immunol. 1992 May;4(5):563–569. [Abstract] [Google Scholar]
  • Minty A, Chalon P, Derocq JM, Dumont X, Guillemot JC, Kaghad M, Labit C, Leplatois P, Liauzun P, Miloux B, et al. Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature. 1993 Mar 18;362(6417):248–250. [Abstract] [Google Scholar]
  • McKenzie AN, Culpepper JA, de Waal Malefyt R, Brière F, Punnonen J, Aversa G, Sato A, Dang W, Cocks BG, Menon S, et al. Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3735–3739. [Europe PMC free article] [Abstract] [Google Scholar]
  • Zurawski G, de Vries JE. Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells. Immunol Today. 1994 Jan;15(1):19–26. [Abstract] [Google Scholar]
  • de Waal Malefyt R, Figdor CG, de Vries JE. Effects of interleukin 4 on monocyte functions: comparison to interleukin 13. Res Immunol. 1993 Oct;144(8):629–633. [Abstract] [Google Scholar]
  • Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med. 1994 Apr 1;179(4):1109–1118. [Europe PMC free article] [Abstract] [Google Scholar]
  • Peters JH, Ruppert J, Gieseler RK, Najar HM, Xu H. Differentiation of human monocytes into CD14 negative accessory cells: do dendritic cells derive from the monocytic lineage? Pathobiology. 1991;59(3):122–126. [Abstract] [Google Scholar]
  • Vercelli D, Jabara HH, Lee BW, Woodland N, Geha RS, Leung DY. Human recombinant interleukin 4 induces Fc epsilon R2/CD23 on normal human monocytes. J Exp Med. 1988 Apr 1;167(4):1406–1416. [Europe PMC free article] [Abstract] [Google Scholar]
  • te Velde AA, Rousset F, Peronne C, De Vries JE, Figdor CG. IFN-alpha and IFN-gamma have different regulatory effects on IL-4-induced membrane expression of Fc epsilon RIIb and release of soluble Fc epsilon RIIb by human monocytes. J Immunol. 1990 Apr 15;144(8):3052–3059. [Abstract] [Google Scholar]
  • te Velde AA, Klomp JP, Yard BA, de Vries JE, Figdor CG. Modulation of phenotypic and functional properties of human peripheral blood monocytes by IL-4. J Immunol. 1988 Mar 1;140(5):1548–1554. [Abstract] [Google Scholar]
  • Becker S, Daniel EG. Antagonistic and additive effects of IL-4 and interferon-gamma on human monocytes and macrophages: effects on Fc receptors, HLA-D antigens, and superoxide production. Cell Immunol. 1990 Sep;129(2):351–362. [Abstract] [Google Scholar]
  • Littman BH, Dastvan FF, Carlson PL, Sanders KM. Regulation of monocyte/macrophage C2 production and HLA-DR expression by IL-4 (BSF-1) and IFN-gamma. J Immunol. 1989 Jan 15;142(2):520–525. [Abstract] [Google Scholar]
  • Gerrard TL, Dyer DR, Mostowski HS. IL-4 and granulocyte-macrophage colony-stimulating factor selectively increase HLA-DR and HLA-DP antigens but not HLA-DQ antigens on human monocytes. J Immunol. 1990 Jun 15;144(12):4670–4674. [Abstract] [Google Scholar]
  • de Waal Malefyt R, Figdor CG, Huijbens R, Mohan-Peterson S, Bennett B, Culpepper J, Dang W, Zurawski G, de Vries JE. Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-gamma or IL-10. J Immunol. 1993 Dec 1;151(11):6370–6381. [Abstract] [Google Scholar]
  • Donnelly RP, Fenton MJ, Kaufman JD, Gerrard TL. IL-1 expression in human monocytes is transcriptionally and posttranscriptionally regulated by IL-4. J Immunol. 1991 May 15;146(10):3431–3436. [Abstract] [Google Scholar]
  • Hart PH, Vitti GF, Burgess DR, Whitty GA, Piccoli DS, Hamilton JA. Potential antiinflammatory effects of interleukin 4: suppression of human monocyte tumor necrosis factor alpha, interleukin 1, and prostaglandin E2. Proc Natl Acad Sci U S A. 1989 May;86(10):3803–3807. [Europe PMC free article] [Abstract] [Google Scholar]
  • Essner R, Rhoades K, McBride WH, Morton DL, Economou JS. IL-4 down-regulates IL-1 and TNF gene expression in human monocytes. J Immunol. 1989 Jun 1;142(11):3857–3861. [Abstract] [Google Scholar]
  • te Velde AA, Huijbens RJ, Heije K, de Vries JE, Figdor CG. Interleukin-4 (IL-4) inhibits secretion of IL-1 beta, tumor necrosis factor alpha, and IL-6 by human monocytes. Blood. 1990 Oct 1;76(7):1392–1397. [Abstract] [Google Scholar]
  • Hamilton JA, Whitty GA, Royston AK, Cebon J, Layton JE. Interleukin-4 suppresses granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor levels in stimulated human monocytes. Immunology. 1992 Aug;76(4):566–571. [Abstract] [Google Scholar]
  • Wieser M, Bonifer R, Oster W, Lindemann A, Mertelsmann R, Herrmann F. Interleukin-4 induces secretion of CSF for granulocytes and CSF for macrophages by peripheral blood monocytes. Blood. 1989 Apr;73(5):1105–1108. [Abstract] [Google Scholar]
  • Suk K, Somers SD, Erickson KL. Regulation of murine macrophage function by IL-4: IL-4 and IFN-gamma differentially regulate macrophage tumoricidal activation. Immunology. 1993 Dec;80(4):617–624. [Abstract] [Google Scholar]
  • Stenger S, Solbach W, Röllinghoff M, Bogdan C. Cytokine interactions in experimental cutaneous leishmaniasis. II. Endogenous tumor necrosis factor-alpha production by macrophages is induced by the synergistic action of interferon (IFN)-gamma and interleukin (IL) 4 and accounts for the antiparasitic effect mediated by IFN-gamma and IL 4. Eur J Immunol. 1991 Jul;21(7):1669–1675. [Abstract] [Google Scholar]
  • Molina IJ, Huber BT. Regulation of macrophage activation markers by IL-4 and IFN-gamma is subpopulation-specific. Cell Immunol. 1991 Apr 15;134(1):241–248. [Abstract] [Google Scholar]
  • Phillips WA, Croatto M, Hamilton JA. The effect of interleukin-4 on the macrophage respiratory burst is species dependent. Biochem Biophys Res Commun. 1992 Jan 31;182(2):727–732. [Abstract] [Google Scholar]
  • Fontaine S, Damais C, Lando D, Cousin MA. Monoclonal antibodies to human interleukin-1 beta and their use in a sensitive two-site enzyme linked immunosorbent assay. Lymphokine Res. 1989 Summer;8(2):129–139. [Abstract] [Google Scholar]
  • Murphy M, Loudon R, Kobayashi M, Trinchieri G. Gamma interferon and lymphotoxin, released by activated T cells, synergize to inhibit granulocyte/monocyte colony formation. J Exp Med. 1986 Jul 1;164(1):263–279. [Europe PMC free article] [Abstract] [Google Scholar]
  • Cuturi MC, Murphy M, Costa-Giomi MP, Weinmann R, Perussia B, Trinchieri G. Independent regulation of tumor necrosis factor and lymphotoxin production by human peripheral blood lymphocytes. J Exp Med. 1987 Jun 1;165(6):1581–1594. [Europe PMC free article] [Abstract] [Google Scholar]
  • Chan SH, Perussia B, Gupta JW, Kobayashi M, Pospísil M, Young HA, Wolf SF, Young D, Clark SC, Trinchieri G. Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med. 1991 Apr 1;173(4):869–879. [Europe PMC free article] [Abstract] [Google Scholar]
  • Chan SH, Kobayashi M, Santoli D, Perussia B, Trinchieri G. Mechanisms of IFN-gamma induction by natural killer cell stimulatory factor (NKSF/IL-12). Role of transcription and mRNA stability in the synergistic interaction between NKSF and IL-2. J Immunol. 1992 Jan 1;148(1):92–98. [Abstract] [Google Scholar]
  • Cassatella MA, Hartman L, Perussia B, Trinchieri G. Tumor necrosis factor and immune interferon synergistically induce cytochrome b-245 heavy-chain gene expression and nicotinamide-adenine dinucleotide phosphate hydrogenase oxidase in human leukemic myeloid cells. J Clin Invest. 1989 May;83(5):1570–1579. [Europe PMC free article] [Abstract] [Google Scholar]
  • Trinchieri G. Interleukin-12 and its role in the generation of TH1 cells. Immunol Today. 1993 Jul;14(7):335–338. [Abstract] [Google Scholar]
  • Trinchieri G. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol. 1995;13:251–276. [Abstract] [Google Scholar]
  • Nagler A, Lanier LL, Phillips JH. The effects of IL-4 on human natural killer cells. A potent regulator of IL-2 activation and proliferation. J Immunol. 1988 Oct 1;141(7):2349–2351. [Abstract] [Google Scholar]
  • Wu CY, Demeure CE, Gately M, Podlaski F, Yssel H, Kiniwa M, Delespesse G. In vitro maturation of human neonatal CD4 T lymphocytes. I. Induction of IL-4-producing cells after long-term culture in the presence of IL-4 plus either IL-2 or IL-12. J Immunol. 1994 Feb 1;152(3):1141–1153. [Abstract] [Google Scholar]
  • Finkelman FD, Madden KB, Cheever AW, Katona IM, Morris SC, Gately MK, Hubbard BR, Gause WC, Urban JF., Jr Effects of interleukin 12 on immune responses and host protection in mice infected with intestinal nematode parasites. J Exp Med. 1994 May 1;179(5):1563–1572. [Europe PMC free article] [Abstract] [Google Scholar]
  • Zlotnik A, Fischer M, Roehm N, Zipori D. Evidence for effects of interleukin 4 (B cell stimulatory factor 1) on macrophages: enhancement of antigen presenting ability of bone marrow-derived macrophages. J Immunol. 1987 Jun 15;138(12):4275–4279. [Abstract] [Google Scholar]
  • Aiello FB, Longo DL, Overton R, Takacs L, Durum SK. A role for cytokines in antigen presentation: IL-1 and IL-4 induce accessory functions of antigen-presenting cells. J Immunol. 1990 Apr 1;144(7):2572–2581. [Abstract] [Google Scholar]
Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

Full text links 

Read article at publisher's site: https://doi.org/10.1084/jem.181.2.537

Read article for free, from open access legal sources, via Unpaywall: https://rupress.org/jem/article-pdf/181/2/537/1106255/537.pdfUnpaywall

Citations & impact 

Impact metrics

201
Citations
Jump to Citations
2
Data citations
Jump to Data

Citations of article over time

Alternative metrics

Altmetric item for https://www.altmetric.com/details/3537984
Altmetric
Discover the attention surrounding your research
https://www.altmetric.com/details/3537984

Article citations

Go to all (201) article citations

Other citations

Data 

Similar Articles 

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

Funding 

Funders who supported this work.

NCI NIH HHS (3)