• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Jul 23, 1996; 93(15): 7849–7854.
PMCID: PMC38837

An essential regulatory role for macrophage migration inhibitory factor in T-cell activation.

Abstract

The protein known as macrophage migration inhibitory factor (MIF) was one of the first cytokines to be discovered and was described 30 years ago to be a T-cell-derived factor that inhibited the random migration of macrophages in vitro. A much broader role for MIF has emerged recently as a result of studies that have demonstrated it to be released from the anterior pituitary gland in vivo. MIF also is the first protein that has been identified to be secreted from monocytes/macrophages upon glucocorticoid stimulation. Once released, MIF acts to "override" or counter-regulate the suppressive effects of glucocorticoids on macrophage cytokine production. We report herein that MIF plays an important regulatory role in the activation of T cells induced by mitogenic or antigenic stimuli. Activated T cells produce MIF and neutralizing anti-MIF antibodies inhibit T-cell proliferation and interleukin 2 production in vitro, and suppress antigen-driven T-cell activation and antibody production in vivo. T cells also release MIF in response to glucocorticoid stimulation and MIF acts to override glucocorticoid inhibition of T-cell proliferation and interleukin 2 and interferon gamma production. These studies indicate that MIF acts in concert with glucocorticoids to control T-cell activation and assign a previously unsuspected but critical role for MIF in antigen-specific immune responses.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.7M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • David JR. Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc Natl Acad Sci U S A. 1966 Jul;56(1):72–77. [PMC free article] [PubMed]
  • Bloom BR, Bennett B. Mechanism of a reaction in vitro associated with delayed-type hypersensitivity. Science. 1966 Jul 1;153(3731):80–82. [PubMed]
  • Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W, Manogue KR, Cerami A, Bucala R. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature. 1993 Oct 21;365(6448):756–759. [PubMed]
  • Nishino T, Bernhagen J, Shiiki H, Calandra T, Dohi K, Bucala R. Localization of macrophage migration inhibitory factor (MIF) to secretory granules within the corticotrophic and thyrotrophic cells of the pituitary gland. Mol Med. 1995 Nov;1(7):781–788. [PMC free article] [PubMed]
  • Calandra T, Bernhagen J, Mitchell RA, Bucala R. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med. 1994 Jun 1;179(6):1895–1902. [PMC free article] [PubMed]
  • Calandra T, Bernhagen J, Metz CN, Spiegel LA, Bacher M, Donnelly T, Cerami A, Bucala R. MIF as a glucocorticoid-induced modulator of cytokine production. Nature. 1995 Sep 7;377(6544):68–71. [PubMed]
  • Bernhagen J, Bacher M, Calandra T, Metz CN, Doty SB, Donnelly T, Bucala R. An essential role for macrophage migration inhibitory factor in the tuberculin delayed-type hypersensitivity reaction. J Exp Med. 1996 Jan 1;183(1):277–282. [PMC free article] [PubMed]
  • Bernhagen J, Mitchell RA, Calandra T, Voelter W, Cerami A, Bucala R. Purification, bioactivity, and secondary structure analysis of mouse and human macrophage migration inhibitory factor (MIF). Biochemistry. 1994 Nov 29;33(47):14144–14155. [PubMed]
  • Kashima N, Nishi-Takaoka C, Fujita T, Taki S, Yamada G, Hamuro J, Taniguchi T. Unique structure of murine interleukin-2 as deduced from cloned cDNAs. Nature. 313(6001):402–404. [PubMed]
  • Miller J, Malek TR, Leonard WJ, Greene WC, Shevach EM, Germain RN. Nucleotide sequence and expression of a mouse interleukin 2 receptor cDNA. J Immunol. 1985 Jun;134(6):4212–4217. [PubMed]
  • Alonso S, Minty A, Bourlet Y, Buckingham M. Comparison of three actin-coding sequences in the mouse; evolutionary relationships between the actin genes of warm-blooded vertebrates. J Mol Evol. 1986;23(1):11–22. [PubMed]
  • Kaye J, Porcelli S, Tite J, Jones B, Janeway CA., Jr Both a monoclonal antibody and antisera specific for determinants unique to individual cloned helper T cell lines can substitute for antigen and antigen-presenting cells in the activation of T cells. J Exp Med. 1983 Sep 1;158(3):836–856. [PMC free article] [PubMed]
  • Lohoff M, Matzner C, Röllinghoff M. Polyclonal B-cell stimulation by L3T4+ T cells in experimental leishmaniasis. Infect Immun. 1988 Aug;56(8):2120–2124. [PMC free article] [PubMed]
  • Schmitt E, Van Brandwijk R, Van Snick J, Siebold B, Rüde E. TCGF III/P40 is produced by naive murine CD4+ T cells but is not a general T cell growth factor. Eur J Immunol. 1989 Nov;19(11):2167–2170. [PubMed]
  • Lohoff M, Schmitt E, Reske-Kunz AB, Röllinghoff M. Different response of TH1 cells for stimulation with anti-CD3 antibodies. Eur J Immunol. 1990 Mar;20(3):653–658. [PubMed]
  • Ullman KS, Northrop JP, Verweij CL, Crabtree GR. Transmission of signals from the T lymphocyte antigen receptor to the genes responsible for cell proliferation and immune function: the missing link. Annu Rev Immunol. 1990;8:421–452. [PubMed]
  • Smith KA, Favata MF, Oroszlan S. Production and characterization of monoclonal antibodies to human interleukin 2: strategy and tactics. J Immunol. 1983 Oct;131(4):1808–1815. [PubMed]
  • Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science. 1976 Sep 10;193(4257):1007–1008. [PubMed]
  • Smith KA, Gillis S, Baker PE, McKenzie D, Ruscetti FW. T-cell growth factor-mediated T-cell proliferation. Ann N Y Acad Sci. 1979;332:423–432. [PubMed]
  • Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed]
  • Mosmann TR, Schumacher JH, Street NF, Budd R, O'Garra A, Fong TA, Bond MW, Moore KW, Sher A, Fiorentino DF. Diversity of cytokine synthesis and function of mouse CD4+ T cells. Immunol Rev. 1991 Oct;123:209–229. [PubMed]
  • Arya SK, Wong-Staal F, Gallo RC. Dexamethasone-mediated inhibition of human T cell growth factor and gamma-interferon messenger RNA. J Immunol. 1984 Jul;133(1):273–276. [PubMed]
  • Gillis S, Crabtree GR, Smith KA. Glucocorticoid-induced inhibition of T cell growth factor production. I. The effect on mitogen-induced lymphocyte proliferation. J Immunol. 1979 Oct;123(4):1624–1631. [PubMed]
  • Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science. 1986 May 23;232(4753):977–980. [PubMed]
  • Knudsen PJ, Dinarello CA, Strom TB. Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells. J Immunol. 1987 Dec 15;139(12):4129–4134. [PubMed]
  • Lew W, Oppenheim JJ, Matsushima K. Analysis of the suppression of IL-1 alpha and IL-1 beta production in human peripheral blood mononuclear adherent cells by a glucocorticoid hormone. J Immunol. 1988 Mar 15;140(6):1895–1902. [PubMed]
  • Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS., Jr Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science. 1995 Oct 13;270(5234):283–286. [PubMed]
  • Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science. 1995 Oct 13;270(5234):286–290. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...