Abstract
The potential effects of macrophage migration inhibitory factor (MIF) on the natural immune response are due to the inhibition of immune cell activation, which is regulated by glucocorticoids. In this study, we investigated MIF −173G/C genotype and C allele frequency in 214 patients with idiopathic nephrotic syndrome (INS) and 103 healthy volunteers. We found significant increases in GC genotype (OR=3, p=0.0009) and C allele frequency (OR=2.5, p=0.0007) in INS. Upon classifying patients as steroid responsive (n=137) or resistant (n=77), a 20-fold over-expression of the CC-genotype was found in the steroid-resistant group (OR=20, p=0.0002). Moreover, a significant increase in C allele frequency in patients with focal segmental glomerulosclerosis (FSGS) has also been noted when compared with other histopathological groups (OR=3.2, p=0.0017). Furthermore, significant increases in the CC genotype (15.6% vs 3.3%) and C allele (75% vs 32%) frequencies have been found in patients with permanent renal function failure (p=0.013 and p=0.0002, respectively). Patients with the CC genotype were found to be at considerably increased risk of permanent renal failure (OR=5.43, p=0.013) and end-stage renal disease (OR=5.53, p=0.020). Additionally, there was a correlation between age of detection of proteinuria and CC genotype. We found an earlier age of onset of proteinuria in patients with the CC genotype (1.9±1.7 years) than in patients who were GC-heterozygous (3.7±3.1 years) and GG-homozygous (3.6±2.9 years, p=0.88). In summary, our results indicate that the MIF −173 C allele confers an increased risk of susceptibility to INS and plays a crucial role in glucocorticoid responsiveness.
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References
Calandra T, Roger T (2003) Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 3:791–800.
Imamura K, Nishihira J, Suzuki M, Yasuda K, Sasaki S, Kusunoki Y, Tochimaru H, Takekoshi Y (1996) Identification and immunohistochemical localization of macrophage migration inhibitory factor in human glomerulonephritis. Biochem Mol Biol Int 40:1233–1242
Lan HY, Yang N, Nikolic-Paterson DJ, Yu XQ, Mu W, Isbel NM, Metz CN, Bucala R, Atkins RC (2000) Expression of macrophage migration inhibitory factor in human glomerulonephritis. Kidney Int 57:499–509
Calandra T, Bernhagen J, Mitchell RA, Bucala R (1994) The macrophage is an important and previously unrecognized source of macrophage inhibitory factor. J Exp Med 179:1985–1992
Bacher M, Metz CN, Calandra T, Mayer K, Chesney J, Lohoff M, Gemsa T, Donnelly T, Bucala R (1996) An essential regulatory role for macrophage migration inhibitory factor in T-cell activation. Proc Natl Acad Sci USA 93:7849–7854
Calandra T, Bernhagen J, Metz CN, Spiegel LA, Bacher M, Donnelly T, Cerami A, Bucala R (1995) MIF as a glucocorticoid-induced modulator of cytokine production. Nature 377:68–71
Donn RP, Ray DW (2004) Macrophage migration inhibitory factor: molecular, cellular and genetic aspects of a key neuroendocrine molecule. J Endocrinol 182:1–9
Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W, Manogue KR, Cerami A, Bucala R (1993) MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 365:756–759
Donn R, Alourfi Z, De Benedetti F, Meazza C, Zeggini E, Lunt M (2002) Mutation screening of the macrophage migration inhibitory factor gene: positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis. Arthritis Rheum 46:2402–2409
Donn R, Alourfi Z, Zeggini E, Lamb R, Jury F, Lunt M, Meazza C, De Benedetti F, Thomson W, Ray D (2004) A functional promoter haplotype of macrophage migration inhibitory factor is linked and associated with juvenile idiopathic arthritis. Arthritis Rheum 50:1604–1610
Nohara H, Okayama N, Inoue N, Koike Y, Fujimura K, Suehiro Y,Hamanaka Y, HigakiS, Yanai H, Yoshida T, Hibi T, Okita K, Hinoda Y (2004) Association of the −173G/C polymorphism of the macrophage migration inhibitory factor gene with ulcerative colitis. J Gastroenterol 39:242–246
Donn RP, Plant D, Jury F, Richards HL, Worthington J, Ray DW, Griffiths CE (2004) Macrophage migration inhibitory factor gene polymorphism is associated with psoriasis. Dermatol J Invest 123:484–487
Makita H, Nishimura M, Miyamoto K, Nakano T, Tanino Y, Hirokawa J, Nishihira J, Kawakami Y (1998) Effect of anti-macrophage migration inhibitory factor antibody on lipopolysaccharide-induced pulmonary neutrophil accumulation. Am J Respir Crit Care Med 158:573–579
Takahashi N, Nishihira J, Sato Y, Kondo M, Ogawa H, Ohshima T, Une Y, Todo S (1998) Involvement of macrophage migration inhibitory factor (MIF) in the mechanism of tumor cell growth. Mol Med 4:707–714
Shimizu T, Abe R, Nakamura H, Ohkawara A, Suzuki M, Nishihira J (1999) High expression of macrophage migration inhibitory factor in human melanoma cells and its role in tumor cell growth and angiogenesis. Biochem Biophys Res Commun 264:751–758
Lolis E (2001) Glucocorticoid counter regulation: macrophage migration inhibitory factor as a target for drug discovery. Curr Opin Pharmacol 1:662–668
Santos L, Hall P, Metz C, Bucala R, Morand EF (2001) Role of macrophage migration inhibitory factor (MIF) in murine antigen-induced arthritis: interaction with glucocorticoids. Clin Exp Immunol 123:309–314
Barton A, Lamb R, Symmons D, Silman A, Thomson W, WorthingtonJ, et al (2003) Macrophage migration inhibitory factor genepolymorphism is associated with susceptibility to but not severity of inflammatory polyarthritis. Genes Immun 4: 487–491
Sasaki S, Nishihira J, Ishibashi T, Yamasaki Y, Obikane K, Echigoya M, Sado Y, Ninomiya Y, Kobayashi K (2004) Transgene of MIF induces podocyte injury and progressive mesangial sclerosis in the mouse kidney. Kidney Int. 65:469–481
Lan HY, Bacher M, Yang N, Mu W, Nicolic-Paterson DJ, Metz C, Meinhardt A, Bucala R, Atkins RC (1997) The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat. J Exp Med 185:1455–1465
Tesch CH, Nikolic-Paterson DJ, Metz CN, Mu W, Bacher M, Bucala R, Atkins RC, Lan HY (1998) Rat mesangial cells express macrophage migration inhibitory factor in vitro and in vivo. J Am Soc Nephrol 9:417–424
Donn RP, Shelley E, Ollier WE, Thomson W (2001) A novel 5′-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 44:1782–1785
Eddy AA, Symons JM (2003) Nephrotic syndrome in childhood. Lancet 362:629–639
Brown FG, Nikolic-Paterson DJ, Hill PA, Isbel NM, Dowling J, Metz CM, Atkins RC (2002) Urine macrophage migration inhibitory factor reflects the severity of renal injury in human glomerulonephritis. J Am Soc Nephrol 13:S7–S13
De Benedetti F, Meazza C, Vivarelli M, Rossi F, Pistorio A, Lamb R, Lunt M, Thomson W, Ravelli A, Donn R, Martini A (2003) Functional and prognostic relevance of the −173 polymorphism of the macrophage migration inhibitory factor gene in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 48: 1398–407
Lue H, Kleemann R, Calandra T, Roger T, Bernhagen J (2002) Macrophage migration inhibitory factor (MIF): mechanisms of action and role in disease. Microbes Infect 4:449–460
Gregersen PK, Bucala R (2003) Macrophage migration inhibitory factor, macrophage migration inhibitory factor alleles, and the genetics of inflammatory disorders: incorporating disease outcome into the definition of phenotype. Arthritis Rheum 48:1171–1176
Baugh JA, Donnelly SC (2003) Macrophage migration inhibitory factor: a neuroendocrine modulator of chronic inflammation. J Endocrinol 179:15–23
Fingerle-Rowson G, Koch P, Bikoff R, Lin X, Metz CN, Dhabhar FS, Meinhardt A, Bucala R (2003) Regulation of macrophage migration inhibitory factor expression by glucocorticoids in vivo. Am J Pathol 162:47–56
Sampey AV, Hall PH, Mitchell RA, Metz CN, Morand EF (2001) Regulation of synoviocyte phospholipase A2 and cyclooxygenase 2 by macrophage migration inhibitory factor. Arthritis Rheum 44: 1273–1280
Kleemann R, Hausser A, Geiger G, Mischke R, Burger-Kentischer A, Flieger O, Johannes FJ, Roger T, Calandra T, Kapurniotu A, Grell M, Finkelmeier D, Brunner H, Bernhagen J (2000) Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1. Nature 408:211–216
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Berdeli, A., Mir, S., Ozkayin, N. et al. Association of macrophage migration inhibitory factor −173C allele polymorphism with steroid resistance in children with nephrotic syndrome. Pediatr Nephrol 20, 1566–1571 (2005). https://doi.org/10.1007/s00467-005-1930-9
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DOI: https://doi.org/10.1007/s00467-005-1930-9