• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of molmedLink to Publisher's site
Mol Med. Jun 1998; 4(6): 413–424.
PMCID: PMC2230272

Reversal of established rat crescentic glomerulonephritis by blockade of macrophage migration inhibitory factor (MIF): potential role of MIF in regulating glucocorticoid production.

Abstract

Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine that also counter-regulates glucocorticoid action. We investigated whether immunoneutralization of MIF could reverse established experimental crescentic glomerulonephritis and if this treatment could modulate endogenous glucocorticoid levels. Accelerated anti-GBM glomerulonephritis was induced in six littermate pairs of rats. Once crescentic disease was established on day 7, one animal in each pair was given a daily injection of neutralizing anti-MIF antibody (Ab) or irrelevant isotype control Ab for 14 days and then killed on day 21. In addition, a group of 6 animals was killed on day 7 of disease without any treatment. Animals receiving the control Ab exhibited a rapidly progressive glomerulonephritis with severe renal injury (proteinuria), loss of renal function (creatinine clearance), anemia, and marked histologic damage (including glomerular crescent formation), compared with animals killed on day 7 without treatment. In contrast, anti-MIF Ab treatment partially reversed the disease by restoring normal renal function and reducing histological damage compared with untreated animals killed on day 7 (p < 0.05). Interestingly, anti-MIF Ab treatment also prevented severe anemia (p < 0.05). Reversal of disease was associated with a significant reduction in leukocyte infiltration and activation and renal interleukin-1 (IL-1) production. Importantly, anti-MIF Ab treatment caused a significant increase in endogenous serum corticosterone levels, which correlated with the reversal of disease parameters. In conclusion, this study has demonstrated that blocking MIF activity can partially reverse established crescentic glomerulonephritis and suggests that MIF operates by both enhancing the cellular immune response and suppressing the endogenous anti-inflammatory glucocorticoid response.

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 (2.8M), 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]
  • Calandra T, Bucala R. Macrophage migration inhibitory factor (MIF): a glucocorticoid counter-regulator within the immune system. Crit Rev Immunol. 1997;17(1):77–88. [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]
  • Bacher M, Metz CN, Calandra T, Mayer K, Chesney J, Lohoff M, Gemsa D, Donnelly T, Bucala R. An essential regulatory role for macrophage migration inhibitory factor in T-cell activation. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7849–7854. [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]
  • 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]
  • Bacher M, Meinhardt A, Lan HY, Mu W, Metz CN, Chesney JA, Calandra T, Gemsa D, Donnelly T, Atkins RC, et al. Migration inhibitory factor expression in experimentally induced endotoxemia. Am J Pathol. 1997 Jan;150(1):235–246. [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]
  • Lan HY, Mu W, Yang N, Meinhardt A, Nikolic-Paterson DJ, Ng YY, Bacher M, Atkins RC, Bucala R. De Novo renal expression of macrophage migration inhibitory factor during the development of rat crescentic glomerulonephritis. Am J Pathol. 1996 Oct;149(4):1119–1127. [PMC free article] [PubMed]
  • Lan HY, Yang N, Metz C, Mu W, Song Q, Nikolic-Paterson DJ, Bacher M, Bucala R, Atkins RC. TNF-alpha up-regulates renal MIF expression in rat crescentic glomerulonephritis. Mol Med. 1997 Feb;3(2):136–144. [PMC free article] [PubMed]
  • Lan HY, Bacher M, Yang N, Mu W, Nikolic-Paterson DJ, Metz C, Meinhardt A, Bucala R, Atkins RC. The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat. J Exp Med. 1997 Apr 21;185(8):1455–1465. [PMC free article] [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]
  • Sunderland CA, McMaster WR, Williams AF. Purification with monoclonal antibody of a predominant leukocyte-common antigen and glycoprotein from rat thymocytes. Eur J Immunol. 1979 Feb;9(2):155–159. [PubMed]
  • Dijkstra CD, Döpp EA, Joling P, Kraal G. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology. 1985 Mar;54(3):589–599. [PMC free article] [PubMed]
  • Damoiseaux JG, Döpp EA, Calame W, Chao D, MacPherson GG, Dijkstra CD. Rat macrophage lysosomal membrane antigen recognized by monoclonal antibody ED1. Immunology. 1994 Sep;83(1):140–147. [PMC free article] [PubMed]
  • Hünig T, Wallny HJ, Hartley JK, Lawetzky A, Tiefenthaler G. A monoclonal antibody to a constant determinant of the rat T cell antigen receptor that induces T cell activation. Differential reactivity with subsets of immature and mature T lymphocytes. J Exp Med. 1989 Jan 1;169(1):73–86. [PMC free article] [PubMed]
  • Tellides G, Dallman MJ, Morris PJ. Mechanism of action of interleukin-2 receptor (IL-2R) monoclonal antibody (MAb) therapy: target cell depletion or inhibition of function? Transplant Proc. 1989 Feb;21(1 Pt 1):997–998. [PubMed]
  • Schotanus K, Holtkamp GM, Meloen RH, Puijk WC, Berkenbosch F, Tilders FJ. Domains of rat interleukin 1 beta involved in type I receptor binding. Endocrinology. 1995 Jan;136(1):332–339. [PubMed]
  • Mitchell R, Bacher M, Bernhagen J, Pushkarskaya T, Seldin MF, Bucala R. Cloning and characterization of the gene for mouse macrophage migration inhibitory factor (MIF). J Immunol. 1995 Apr 15;154(8):3863–3870. [PubMed]
  • Lan HY, Paterson DJ, Atkins RC. Initiation and evolution of interstitial leukocytic infiltration in experimental glomerulonephritis. Kidney Int. 1991 Sep;40(3):425–433. [PubMed]
  • Lan HY, Nikolic-Paterson DJ, Zarama M, Vannice JL, Atkins RC. Suppression of experimental crescentic glomerulonephritis by the interleukin-1 receptor antagonist. Kidney Int. 1993 Feb;43(2):479–485. [PubMed]
  • Lan HY, Nikolic-Paterson DJ, Mu W, Atkins RC. Local macrophage proliferation in the progression of glomerular and tubulointerstitial injury in rat anti-GBM glomerulonephritis. Kidney Int. 1995 Sep;48(3):753–760. [PubMed]
  • Lan HY, Zarama M, Nikolic-Paterson DJ, Kerr PG, Atkins RC. Suppression of experimental crescentic glomerulonephritis by deoxyspergualin. J Am Soc Nephrol. 1993 May;3(11):1765–1774. [PubMed]
  • Yu XQ, Nikolic-Paterson DJ, Mu W, Giachelli CM, Atkins RC, Johnson RJ, Lan HY. A functional role for osteopontin in experimental crescentic glomerulonephritis in the rat. Proc Assoc Am Physicians. 1998 Jan-Feb;110(1):50–64. [PubMed]
  • Nikolic-Paterson DJ, Lan HY, Hill PA, Vannice JL, Atkins RC. Suppression of experimental glomerulonephritis by the interleukin-1 receptor antagonist: inhibition of intercellular adhesion molecule-1 expression. J Am Soc Nephrol. 1994 Mar;4(9):1695–1700. [PubMed]
  • Tang WW, Feng L, Vannice JL, Wilson CB. Interleukin-1 receptor antagonist ameliorates experimental anti-glomerular basement membrane antibody-associated glomerulonephritis. J Clin Invest. 1994 Jan;93(1):273–279. [PMC free article] [PubMed]
  • Tang WW, Qi M, Warren JS. Monocyte chemoattractant protein 1 mediates glomerular macrophage infiltration in anti-GBM Ab GN. Kidney Int. 1996 Aug;50(2):665–671. [PubMed]
  • MacPhee IA, Antoni FA, Mason DW. Spontaneous recovery of rats from experimental allergic encephalomyelitis is dependent on regulation of the immune system by endogenous adrenal corticosteroids. J Exp Med. 1989 Feb 1;169(2):431–445. [PMC free article] [PubMed]
  • Lacombe C, Da Silva JL, Bruneval P, Fournier JG, Wendling F, Casadevall N, Camilleri JP, Bariety J, Varet B, Tambourin P. Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney. J Clin Invest. 1988 Feb;81(2):620–623. [PMC free article] [PubMed]
  • Maxwell PH, Ferguson DJ, Nicholls LG, Johnson MH, Ratcliffe PJ. The interstitial response to renal injury: fibroblast-like cells show phenotypic changes and have reduced potential for erythropoietin gene expression. Kidney Int. 1997 Sep;52(3):715–724. [PubMed]
  • Eschbach JW. The anemia of chronic renal failure: pathophysiology and the effects of recombinant erythropoietin. Kidney Int. 1989 Jan;35(1):134–148. [PubMed]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...