Objective: We evaluated the changes in the migration inhibitory factor (MIF) expression with time in the bladder and spinal cord of a Sprague-Dawley rat cystitis model. Methods: The bladder created by injecting lipopolysaccharide (LPS) and the lumbosacral spinal cord were removed at 4, 24, and 48 h, and 7 days after the induction of chronic cystitis, and 24 h after the induction of acute cystitis. The MIF expression was estimated using immunohistochemical staining, and the MIF mRNA was quantitatively analyzed using real-time polymerase chain reaction. Results: The MIF expression in the urothelial cell was lowest at 24 h after LPS injection. As the degree of inflammation decreased, the MIF expression in the urothelial cell gradually increased 48 h and 7 days. The quantitative analysis of the MIF mRNA showed that the MIF expression was highest in both the bladder and the lumbosacral spinal cord 24 h after the cystitis became most severe. In chronic cystitis, the MIF mRNA expressions in the bladder and the lumbosacral spinal cord were 2.8 and 2.1 times significantly higher than in the normal control. Conclusion: MIF is involved in urinary symptoms and pain in cystitis, and in the mechanism that prolongs the symptoms of chronic cystitis by involving bladder tissue, and the nervous system.

1.
Nathan CF, Karnovsky ML, David JR: Alterations of macrophage functions by mediators from lymphocytes. J Exp Med 1971;133:1356-1376.
2.
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;377:68-71.
3.
Baugh JA, Bucala R: Macrophage migration inhibitory factor. Crit Care Med 2002;30(1 suppl):S27-S35.
4.
Vera PL, Ordorica RC, Meyer-Siegler KL: Hydrochloric acid induced changes in macrophage migration inhibitory factor in the bladder, peripheral and central nervous system of the rat. J Urol 2003;170(2 pt 1):623-627.
5.
Wang F, Shen X, Guo X, Peng Y, Liu Y, Xu S, Yang J: Spinal macrophage migration inhibitory factor contributes to the pathogenesis of inflammatory hyperalgesia in rats. Pain 2010;148:275-283.
6.
Saban MR, Nguyen NB, Hammond TG, Saban R: Gene expression profiling of mouse bladder inflammatory responses to LPS, substance P, and antigen-stimulation. Am J Pathol 2002;160:2095-2110.
7.
Dupont MC, Spitsbergen JM, Kim KB, Tuttle JB, Steers WD: Histological and neurotrophic changes triggered by varying models of bladder inflammation. J Urol 2001;166:1111-1118.
8.
Bacher M, Meinhardt A, Lan HY, Mu W, Metz CN, Chesney JA, Calandra T, Gemsa D, Donnelly T, Atkins RC, Bucala R: Migration inhibitory factor expression in experimentally induced endotoxemia. Am J Pathol 1997;150:235-246.
9.
Gregersen PK, Bucala R: Macrophage migration inhibitory factor, MIF alleles, and the genetics of inflammatory disorders: incorporating disease outcome into the definition of phenotype. Arthritis Rheum 2003;48:1171-1176.
10.
Leech M, Metz C, Bucala R, Morand EF: Regulation of macrophage migration inhibitory factor by endogenous glucocorticoids in rat adjuvant-induced arthritis. Arthritis Rheum 2000;43:827-833.
11.
Leech M, Metz C, Hall P, Hutchinson P, Gianis K, Smith M, Weedon H, Holdsworth SR, Bucala R, Morand EF: Macrophage migration inhibitory factor in rheumatoid arthritis: evidence of proinflammatory function and regulation by glucocorticoids. Arthritis Rheum 1999;42:1601-1608.
12.
Mitchell RA, Metz CN, Peng T, Bucala R: Sustained mitogen-activated protein kinase (MAPK) and cytoplasmic phospholipase A2 activation by macrophage migration inhibitory factor (MIF). Regulatory role in cell proliferation and glucocorticoid action. J Biol Chem 1999;274:18100-18106.
13.
Baugh JA, Donnelly SC: Macrophage migration inhibitory factor: a neuroendocrine modulator of chronic inflammation. J Endocrinol 2003;179:15-23.
14.
Donn RP, Ray DW: Macrophage migration inhibitory factor: molecular, cellular and genetic aspects of a key neuroendocrine molecule. J Endocrinol 2004;182:1-9.
15.
Morand EF: New therapeutic target in inflammatory disease: macrophage migration inhibitory factor. Intern Med J 2005;35:419-426.
16.
Otukesh H, Fereshtehnejad SM, Hoseini R, Hekmat S, Chalian H, Chalian M, Bedayat A, Salman Yazdi R, Sabaghi S, Mahdavi S: Urine macrophage migration inhibitory factor (MIF) in children with urinary tract infection: a possible predictor of acute pyelonephritis. Pediatr Nephrol 2009;24:105-111.
17.
Meyer-Siegler KL, Leifheit EC, Vera PL: Inhibition of macrophage migration inhibitory factor decreases proliferation and cytokine expression in bladder cancer cells. BMC Cancer 2004;4:34.
18.
Vera PL, Meyer-Siegler KL: Anatomical location of macrophage migration inhibitory factor in urogenital tissues, peripheral ganglia and lumbosacral spinal cord of the rat. BMC Neurosci 2003;4:17.
19.
Meyer-Siegler KL, Ordorica RC, Vera PL: Macrophage migration inhibitory factor is upregulated in an endotoxin-induced model of bladder inflammation in rats. J Interferon Cytokine Res 2004;24:55-63.
20.
Meyer-Siegler KL, Vera PL: Substance P induced release of macrophage migration inhibitory factor from rat bladder epithelium. J Urol 2004;171:1698-1703.
21.
Leng L, Metz CN, Fang Y, Xu J, Donnelly S, Baugh J, Delohery T, Chen Y, Mitchell RA, Bucala R: MIF signal transduction initiated by binding to CD74. J Exp Med 2003;197:1467-1476.
22.
Meyer-Siegler KL, Vera PL: Substance P induced changes in CD74 and CD44 in the rat bladder. J Urol 2005;173:615-620.
23.
Shi X, Leng L, Wang T, Wang W, Du X, Li J, McDonald C, Chen Z, Murphy JW, Lolis E, Noble P, Knudson W, Bucala R: CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. Immunity 2006;25:595-606.
24.
Meyer-Siegler KL, Vera PL: Intraluminal antibodies to macrophage migration inhibitory factor decrease substance p induced inflammatory changes in the rat bladder and prostate. J Urol 2004;172(4 pt 1):1504-1509.
25.
Watkins LR, Maier SF: Implications of immune-to-brain communication for sickness and pain. Proc Natl Acad Sci U S A 1999;96:7710-7713.
26.
Shimizu T, Nishihira J, Watanabe H, Abe R, Honda A, et al: Macrophage migration inhibitory factor is induced by thrombin and factor Xa in endothelial cells. J Biol Chem 2004;279:13729-13737.
27.
Meyer-Siegler KL, Ordorica RC, Vera PL: Macrophage migration inhibitory factor is upregulated in an endotoxin-induced model of bladder inflammation in rats. J Interferon Cytokine Res 2004;24:55-63.
28.
Kouzoukas DE, Meyer-Siegler KL, Ma F, Westlund KN, Hunt DE, Vera PL: Macrophage migration inhibitory factor mediates PAR-induced bladder pain. PLoS One 2015;10:e0127628.
29.
Kouzoukas DE, Ma F, Meyer-Siegler KL, Westlund KN, Hunt DE, Vera PL: Protease-activated receptor 4 induces bladder pain through high mobility group Box-1. PLoS One 2016;11:e0152055.
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