Summary
IL-4, a product of the T-helper 0 (Th0) and 2 (Th2) subset, was originally described as a B-cell stimulatory factor and has subsequently been found to suppress IL-1α, IL-1Β, IL-6, IL-8, and TNF-α gene expression in monocytes stimulated with LPS, and to upregulate IL-1 receptor antagonist (IL1-RA) gene expression. In this study we investigated the effect of IL-4 on the expression of cytokine genes in monocytes evoked by other T-helper cell cytokines: IL-2, IL-3, and GM-CSF. IL-4 down-regulated mRNA accumulation of the proinflammatory cytokines IL-1Β, IL-8, and TNF-α in monocytes stimulated with IL-2, IL-3, and GM-CSF. IL-4 also suppressed the IL-2-induced IL-6 mRNA expression. Temporal analysis of the IL-4 down-regulatory effect on the IL-2-, IL-3-, or GM-CSF — induced proinflammatory cytokine gene expression in monocytes provided evidence that IL-4 acts predominantly oh the post-transcriptional level. This was supported by the observation that the down-regulatory capacity of IL-4 appeared to be dependent on de novo protein synthesis. IL-4 did not exert significant influence on the induction of expression of IL-1-RA or various CSFs by IL-2, IL-3, and GM-CSF. We hypothesize that owing to its being a down-regulator of the expression of proinflammatory cytokines induced by IL-2, IL-3, and GM-CSF — products of activated ThO or Th1 cells —together with its capacity as a B-cell stimulatory factor, IL-4 has an important role in directing the immune response.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Street NE, Mosmann TR (1991) Functional diversity of T lymphocytes due to secretion of different cytokine patterns. FASEB J 5:171
Romagnani S (1992) Human Th1 and Th2 subsets: doubt no more. Immunol Today 12:256
Cluitmans FHM, Esendam BHJ, Landegent JE, Willemze R, Falkenburg JHF (1993) Regulatory effects of T cell lymphokines on cytokine gene expression in monocytes. Lymphokine Cytokine Res 12:457
Paul WE (1991) Interleukin-4: prototypic immunoregulatory lymphokine. Blood 77:1859
Jansen JH, Fibbe WE, Willemze R, Kluin Nelemans JC (1990) Interleukin-4: a regulatory protein. Blut 60:269
Essner R, Rhoades K, McBride WH, Morton DL, Economou JS (1990) IL-4 down-regulates IL-1 and TNF gene expression in human monocytes. J Immunol 142:3857
Lee JD, Swisher SG, Minehart EH, McBride WH, Economou JS (1990) Interleukin-4 downregulates Interleukin-6 production in human peripheral blood mononuclear cells. J Leukocyte Biol 47:475
Standiford TJ, Strieter RM, Chensue SW, Westwick J, Kasahara K, Kunkel SL (1990) IL-4 inhibits the expression of IL-8 from stimulated human monocytes. J Immunol 145:1435
Orino O, Sone S, Nii A, Ogura T (1992) IL-4 up-regulates IL-1 receptor antagonist gene expression and its production in human blood monocytes. J Immunol 149:925
Fenton MJ, Buras JA, Donnelly RP (1992) IL-4 reciprocally regulates IL-1 and IL-1 receptor antagonist expression in human monocytes. J Immunol 149:1283
Wong HL, Costa GL, Lotze ML, Wahl SM (1993) Interleukin (IL) 4 differentially regulates monocyte IL-1 family gene expression and synthesis in vitro and in vivo. J Exp Med 177:775
Wieser M, Bonifer R, Oster W, Lindemann A, Mertelsmann R, Herrmann F (1989) Interleukin-4 induces secretion of CSF for granulocytes and CSF for macrophages by peripheral blood monocytes. Blood 73:1105
Hamilton JA, Whitty GA, Royston AKM, Cebon J, Layton JE (1992) Interleukin-4 suppresses granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor levels in stimulated human monocytes. Immunology 76:566
Plas A, De Witte T, Wessels H, Haanen C (1988) A new multichamber counterflow centrifugation rotor with high-separation capacity and versatile potentials. Exp Hematol 16:355
Falkenburg JHF, Harrington MA, De Paus RA, Walsh WK, Daub R, Landegent JE, Broxmeyer HE (1991) Differential transcriptional and posttranscriptional regulation of gene expression of the colony-stimulating factors by interleukin-1 and fetal bovine serum in murine fibroblasts. Blood 78:658
Kaashoek JGJ, Mout R, Falkenburg JHF, Willemze R, Fibbe WE, Landegent JE (1991) Cytokine production by the bladder carcinoma cell line 5637: rapid analysis of mRNA expression levels using a cDNA-PCR procedure. Lymphokine Cytokine Res 10:231
Donnelly RP, Fenton MJ, Kaufman JD, Gerrard TL (1991) IL-1 expression in human monocytes is transcriptionally and posttranscriptionally regulated by IL-4. J Immunol 146:3431
Shaw G, Kamen R (1986) A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 46:659
Caput D, Beutler B, Hartog K, Thayer R, Brown-Shimer S, Cerami A (1986) Identification of a common nucleotide sequence in the 3′ untranslated region of mRNA molecules specifying inflammatory mediators. Proc Natl Acad Sci USA 83:1670
Van Deventer SJH, Buller HR, Ten Cate JW, Sturk A, Pauw W (1988) Endotoxaemia: an early predictor of septicaemia in febrile patients. Lancet 1:605
Waage A, Brandtzaeg P, Halstensen A, Kierulf P, Espevik T (1989) The complex pattern of cytokines in serum from patients with meningococcal septic shock. J Exp Med 169:333
Damas P, Reuter A, Gysen P, Demonty J, Lamy M, Franchimont P (1989) Tumor necrosis factor and interleukin-1 serum levels during severe sepsis in humans. Crit Care Med 17:975
Mitchie HR, Manogue KR, Spriggs DR (1988) Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 318:1481
Spooner EC, Markowitz NP, Saravolatz LD (1992) The role of tumor necrosis factor in sepsis. Clin Immunol Immunopathol 62:S12
Ohlsson K, Björk P, Bergenfeldt M, Hageman R, Thompson RC (1990) Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature 348:550
Alexander HR, Doherty GM, Buresh CM, Venzon DJ, Norton JA (1991) A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice. J Exp Med 173:1029
Bogen SA, Fogelman I, Abbas AK (1993) Analysis of IL-2, IL-4, and IFN-γ producing cells in situ during immune responses to protein antigens. J Immunol 150:4197
Zumla A (1992) Superantigens, T cells, and microbes. Clin Infect Dis 15:313
See RH, Kum WWS, Chang AH, Goh SH, Chow AW (1992) Induction of tumor necrosis factor and interleukin-1 by purified staphylococcal toxic shock syndrome toxin 1 requires the presence of both monocytes and T lymphocytes. Infect Immun 60:2612
Kuhns DB, DeCarlo E, Hawk DM, Gallin JI (1992) Dynamics of the cellular and humoral components of the inflammatory response elicited in skin blisters in humans. J Clin Invest 89:1734
Author information
Authors and Affiliations
Additional information
This study was supported in part by gramts from the J.A. Cohen Institute for Radiopathology and Radiation Protection J. H. F. Falkenburg is a Special Fellow of the Royal Netherlands Academy of Arts and Sciences
Rights and permissions
About this article
Cite this article
Cluitmans, F.H.M., Esendam, B.H.J., Landegent, J.E. et al. IL-4 down-regulates IL-2-, IL-3-, and GM-CSF-induced cytokine gene expression in peripheral blood monocytes. Ann Hematol 68, 293–298 (1994). https://doi.org/10.1007/BF01695035
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01695035