Macrophage migration inhibitory factor polymorphisms are a potential susceptibility marker in systemic sclerosis from southern Mexican population: association with MIF mRNA expression and cytokine profile

  • Christian Johana Baños-Hernández
  • José Eduardo Navarro-Zarza
  • Richard Bucala
  • Jorge Hernández-Bello
  • Isela Parra-Rojas
  • María Guadalupe Ramírez-Dueñas
  • Samuel García-Arellano
  • Luis Alexis Hernández-Palma
  • Andrea Carolina Machado-Sulbarán
  • José Francisco Muñoz-ValleEmail author
Original Article



Systemic sclerosis (SSc) is a complex autoimmune disease, characterized by microvascular lesions, autoimmunity, and fibrosis. It is suggested that MIF participates in the amplification of the proinflammatory process in SSc; moreover, the promoter polymorphisms − 794 CATT5–8 (rs5844572) and − 173G>C (rs755622) in the MIF gene have been associated with an increase in MIF serum levels in several autoimmune diseases. The aim of this study was to analyze the relationship of the − 794 CATT5–8 and − 173G>C MIF polymorphisms with mRNA expression, MIF serum levels, and the Th1/Th2/Th17 cytokine profile in SSc.

Materials and methods

A case-control study was carried out that included 50 patients with SSc and 100 control subjects (CS). Both polymorphisms were genotyped by PCR and PCR-RFLP. MIF levels were measured by ELISA kit. The cytokine profile and the MIF mRNA expression were quantified by BioPlex MagPix system and real-time PCR, respectively.


An association between the − 794 CATT7 and − 173*C MIF alleles and the 7C haplotype with SSc susceptibility was found (p < 0.05). Also, the 7C haplotype was associated with increased MIF mRNA expression (p = 0.03) in SSc. In addition, an increase of IL-1β and IL-6 serum levels in SSc patients was found as well as a positive correlation between MIF serum levels and Th1 and Th17 cytokine profiles.


The MIF 7C haplotype is a susceptibility marker for SSc in the southern Mexican population and is associated with MIF mRNA expression. Moreover, there is a positive correlation between MIF serum levels and Th1 and Th17 inflammatory response in SSc.


Cytokine profiles Th1/Th2/Th17 MIF MIF mRNA expression Promoter polymorphisms Systemic sclerosis 


Funding information

The study was supported by funding from the National Council of Science and Technology (CONACYT) Grant A1-S-8774 (CONACYT Ciencia Básica-Universidad de Guadalajara) assigned to JFMV. Also, CJH-B was a Ph.D. fellow at CONACYT-Mexico (#301502).

Compliance with ethical standards

Informed written consent was obtained from all subjects before enrollment to the study. The investigation was performed according to the ethical guidelines of the 2013 Declaration of Helsinki and was approved by the ethical, investigation, and biosecurity committee of the Hospital General de Chilpancingo “Dr. Raymundo Abarca Alarcón,” Chilpancingo de los Bravo, State of Guerrero, Mexico (CI/317/2016).




  1. 1.
    Barsotti S, Stagnaro C, d'Ascanio A et al (2016) One year in review 2016: systemic sclerosis. Clin Exp Rheumatol 34 Suppl 100(5):3–13Google Scholar
  2. 2.
    van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, Allanore Y, Furst DE, Gabrielli A, Mayes MD, van Laar JM, Seibold JR, Czirjak L, Steen VD, Inanc M, Kowal-Bielecka O, Müller-Ladner U, Valentini G, Veale DJ, Vonk MC, Walker UA, Chung L, Collier DH, Csuka ME, Fessler BJ, Guiducci S, Herrick A, Hsu VM, Jimenez S, Kahaleh B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, Pope JE (2013) 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European league against rheumatism collaborative initiative. Arthritis Rheum 65(11):2737–2747Google Scholar
  3. 3.
    Katsumoto TR, Whitfield ML, Connolly MK (2011) The pathogenesis of systemic sclerosis. Annu Rev Pathol 6:509–537Google Scholar
  4. 4.
    Stern EP, Denton CP (2015) The pathogenesis of systemic sclerosis. Rheum Dis Clin N Am 41(3):367–382Google Scholar
  5. 5.
    Selvi E, Tripodi SA, Catenaccio M, Lorenzini S, Chindamo D, Manganelli S, Romagnoli R, Ietta F, Paulesu L, Miracco C, Cintorino M, Marcolongo R (2003) Expression of macrophage migration inhibitory factor in diffuse systemic sclerosis. Ann Rheum Dis 62(5):460–464Google Scholar
  6. 6.
    Ramos PS, Silver RM, Feghali-Bostwick CA (2015) Genetics of systemic sclerosis: recent advances. Curr Opin Rheumatol 27(6):521–529Google Scholar
  7. 7.
    Calandra T, Roger T (2003) Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 3(10):791–800Google Scholar
  8. 8.
    Mitchell RA, Liao H, Chesney J, Fingerle-Rowson G, Baugh J, David J, Bucala R (2002) Macrophage migration inhibitory factor (MIF) sustains macrophage proinflammatory function by inhibiting p53: regulatory role in the innate immune response. Proc Natl Acad Sci U S A 99(1):345–350Google Scholar
  9. 9.
    Kim JY, Kwok SK, Hur KH, Kim HJ, Kim NS, Yoo SA, Kim WU, Cho CS (2008) Up-regulated macrophage migration inhibitory factor protects apoptosis of dermal fibroblasts in patients with systemic sclerosis. Clin Exp Immunol 152(2):328–335Google Scholar
  10. 10.
    Llamas-Covarrubias MA, Valle Y, Bucala R, Navarro-Hernández RE, Palafox-Sánchez CA, Padilla-Gutiérrez JR, Parra-Rojas I, Bernard-Medina AG, Reyes-Castillo Z, Muñoz-Valle JF (2013) Macrophage migration inhibitory factor (MIF): genetic evidence for participation in early onset and early stage rheumatoid arthritis. Cytokine 61(3):759–765Google Scholar
  11. 11.
    Morales-Zambrano R, Bautista-Herrera LA, De la Cruz-Mosso U et al (2014) Macrophage migration inhibitory factor (MIF) promoter polymorphisms (−794 CATT5-8 and −173 G>C): association with MIF and TNFalpha in psoriatic arthritis. Int J Clin Exp Med 7(9):2605–2614Google Scholar
  12. 12.
    De la Cruz-Mosso U, Bucala R, Palafox-Sanchez CA et al (2014) Macrophage migration inhibitory factor: association of −794 CATT5-8 and −173 G>C polymorphisms with TNF-alpha in systemic lupus erythematosus. Hum Immunol 75(5):433–439Google Scholar
  13. 13.
    Castaneda-Moreno VA, De la Cruz-Mosso U, Torres-Carrillo N et al (2018) MIF functional polymorphisms (−794 CATT5-8 and −173 G>C) are associated with MIF serum levels, severity and progression in male multiple sclerosis from western Mexican population. J Neuroimmunol 320:117–124Google Scholar
  14. 14.
    Baugh JA, Chitnis S, Donnelly SC, Monteiro J, Lin X, Plant BJ, Wolfe F, Gregersen PK, Bucala R (2002) A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis. Genes Immun 3(3):170–176Google Scholar
  15. 15.
    Yao J, Leng L, Sauler M, Fu W, Zheng J, Zhang Y, du X, Yu X, Lee P, Bucala R (2016) Transcription factor ICBP90 regulates the MIF promoter and immune susceptibility locus. J Clin Invest 126(2):732–744Google Scholar
  16. 16.
    Gregersen PK, Bucala R (2003) Macrophage migration inhibitory factor, MIF alleles, and the genetics of inflammatory disorders: incorporating disease outcome into the definition of phenotype. Arthritis Rheum 48(5):1171–1176Google Scholar
  17. 17.
    Wu SP, Leng L, Feng Z, Liu N, Zhao H, McDonald C, Lee A, Arnett FC, Gregersen PK, Mayes MD, Bucala R (2006) Macrophage migration inhibitory factor promoter polymorphisms and the clinical expression of scleroderma. Arthritis Rheum 54(11):3661–3669Google Scholar
  18. 18.
    Bossini-Castillo L, Simeon CP, Beretta L, Vonk MC, Callejas-Rubio JL, Espinosa G, Carreira P, Camps MT, Rodríguez-Rodríguez L, Rodríguez-Carballeira M, García-Hernández FJ, López-Longo FJ, Hernández-Hernández V, Sáez-Comet L, Egurbide MV, Hesselstrand R, Nordin A, Hoffmann-Vold AM, Vanthuyne M, Smith V, de Langhe E, Kreuter A, Riemekasten G, Witte T, Hunzelmann N, Voskuyl AE, Schuerwegh AJ, Lunardi C, Airó P, Scorza R, Shiels P, van Laar JM, Fonseca C, Denton C, Herrick A, Worthington J, Koeleman BP, Rueda B, Radstake TRDJ, Martin J (2011) Confirmation of association of the macrophage migration inhibitory factor gene with systemic sclerosis in a large European population. Rheumatology 50(11):1976–1981Google Scholar
  19. 19.
    Becker H, Willeke P, Schotte H, Domschke W, Gaubitz M (2008) Macrophage migration inhibitory factor may contribute to vasculopathy in systemic sclerosis. Clin Rheumatol 27(10):1307–1311Google Scholar
  20. 20.
    Ningyan G, Xu Y, Hongfei S, Jingjing C, Min C (2015) The role of macrophage migration inhibitory factor in mast cell-stimulated fibroblast proliferation and collagen production. PLoS One 10(3):e0122482Google Scholar
  21. 21.
    Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215Google Scholar
  22. 22.
    Radstake TR, Sweep FC, Welsing P et al (2005) Correlation of rheumatoid arthritis severity with the genetic functional variants and circulating levels of macrophage migration inhibitory factor. Arthritis Rheum 52(10):3020–3029Google Scholar
  23. 23.
    Makhija R, Kingsnorth A, Demaine A (2007) Gene polymorphisms of the macrophage migration inhibitory factor and acute pancreatitis. JOP 8(3):289–295Google Scholar
  24. 24.
    Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162(1):156–159Google Scholar
  25. 25.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25(4):402–408Google Scholar
  26. 26.
    Shi YY, He L (2005) SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 15(2):97–98Google Scholar
  27. 27.
    Hong EP, Park JW (2012) Sample size and statistical power calculation in genetic association studies. Genomics Inform 10(2):117–122Google Scholar
  28. 28.
    Faul F, Erdfelder E, Buchner A, Lang AG (2009) Statistical power analyses using G*power 3.1: tests for correlation and regression analyses. Behav Res Methods 41(4):1149–1160Google Scholar
  29. 29.
    Purcell S, Cherny SS, Sham PC (2003) Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19(1):149–150Google Scholar
  30. 30.
    Mayes MD, Bossini-Castillo L, Gorlova O, Martin JE, Zhou X, Chen WV, Assassi S, Ying J, Tan FK, Arnett FC, Reveille JD, Guerra S, Teruel M, Carmona FD, Gregersen PK, Lee AT, López-Isac E, Ochoa E, Carreira P, Simeón CP, Castellví I, González-Gay MÁ, Zhernakova A, Padyukov L, Alarcón-Riquelme M, Wijmenga C, Brown M, Beretta L, Riemekasten G, Witte T, Hunzelmann N, Kreuter A, Distler JHW, Voskuyl AE, Schuerwegh AJ, Hesselstrand R, Nordin A, Airó P, Lunardi C, Shiels P, van Laar JM, Herrick A, Worthington J, Denton C, Wigley FM, Hummers LK, Varga J, Hinchcliff ME, Baron M, Hudson M, Pope JE, Furst DE, Khanna D, Phillips K, Schiopu E, Segal BM, Molitor JA, Silver RM, Steen VD, Simms RW, Lafyatis RA, Fessler BJ, Frech TM, AlKassab F, Docherty P, Kaminska E, Khalidi N, Jones HN, Markland J, Robinson D, Broen J, Radstake TRDJ, Fonseca C, Koeleman BP, Martin J, Ortego-Centeno N, Ríos R, Callejas JL, Navarrete N, García Portales R, Camps MT, Fernández-Nebro A, González-Escribano MF, Sánchez-Román J, García-Hernández FJ, Castillo MJ, Aguirre MÁ, Gómez-Gracia I, Fernández-Gutiérrez B, Rodríguez-Rodríguez L, Vicente E, Andreu JL, Fernández de Castro M, García de la Peña P, López-Longo FJ, Martínez L, Fonollosa V, Espinosa G, Tolosa C, Pros A, Rodríguez Carballeira M, Narváez FJ, Rubio Rivas M, Ortiz Santamaría V, Díaz B, Trapiella L, Freire MC, Sousa A, Egurbide MV, Fanlo Mateo P, Sáez-Comet L, Díaz F, Hernández V, Beltrán E, Román-Ivorra JA, Grau E, Alegre Sancho JJ, Blanco García FJ, Oreiro N, Fernández Sueiro L (2014) Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis. Am J Hum Genet 94(1):47–61Google Scholar
  31. 31.
    Sreih A, Ezzeddine R, Leng L, LaChance A, Yu G, Mizue Y, Subrahmanyan L, Pons-Estel BA, Abelson AK, Gunnarsson I, Svenungsson E, Cavett J, Glenn S, Zhang L, Montgomery R, Perl A, Salmon J, Alarcón-Riquelme ME, Harley JB, Bucala R (2011) Dual effect of the macrophage migration inhibitory factor gene on the development and severity of human systemic lupus erythematosus. Arthritis Rheum 63(12):3942–3951Google Scholar
  32. 32.
    Norton BJ, Strube MJ (2001) Understanding statistical power. J Orthop Sports Phys Ther 31(6):307–315Google Scholar
  33. 33.
    Button KS, Ioannidis JP, Mokrysz C et al (2013) Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci 14(5):365–376Google Scholar
  34. 34.
    Bryc K, Durand EY, Macpherson JM, Reich D, Mountain JL (2015) The genetic ancestry of African Americans, Latinos, and European Americans across the United States. Am J Hum Genet 96(1):37–53Google Scholar
  35. 35.
    Roy-Gagnon MH, Moreau C, Bherer C, St-Onge P, Sinnett D, Laprise C, Vézina H, Labuda D (2011) Genomic and genealogical investigation of the French Canadian founder population structure. Hum Genet 129(5):521–531Google Scholar
  36. 36.
    Martinez-Cortes G, Salazar-Flores J, Fernandez-Rodriguez LG et al (2012) Admixture and population structure in Mexican-mestizos based on paternal lineages. J Hum Genet 57(9):568–574Google Scholar
  37. 37.
    Corallo C, Paulesu L, Cutolo M, Ietta F, Carotenuto C, Mannelli C, Romagnoli R, Nuti R, Giordano N (2015) Serum levels, tissue expression and cellular secretion of macrophage migration inhibitory factor in limited and diffuse systemic sclerosis. Clin Exp Rheumatol 33(4 Suppl 91):S98–S105Google Scholar
  38. 38.
    Karres I, Kremer JP, Dietl I et al (1998) Chloroquine inhibits proinflammatory cytokine release into human whole blood. Am J Phys 274(4 Pt 2):R1058–R1064Google Scholar
  39. 39.
    Church TS, Willis MS, Priest EL, LaMonte MJ, Earnest CP, Wilkinson WJ, Wilson DA, Giroir BP (2005) Obesity, macrophage migration inhibitory factor, and weight loss. Int J Obes 29(6):675–681Google Scholar
  40. 40.
    Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444(7121):860–867Google Scholar
  41. 41.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112(12):1796–1808Google Scholar
  42. 42.
    Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112(12):1821–1830Google Scholar
  43. 43.
    Dandona P, Aljada A, Ghanim H, Mohanty P, Tripathy C, Hofmeyer D, Chaudhuri A (2004) Increased plasma concentration of macrophage migration inhibitory factor (MIF) and MIF mRNA in mononuclear cells in the obese and the suppressive action of metformin. J Clin Endocrinol Metab 89(10):5043–5047Google Scholar
  44. 44.
    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(6544):68–71Google Scholar
  45. 45.
    Kamchybekov U, Figulla HR, Gerdes N, Jung C (2012) Macrophage migration inhibitory factor is elevated in obese adolescents. Arch Physiol Biochem 118(4):204–209Google Scholar
  46. 46.
    Llamas-Covarrubias MA, Valle Y, Navarro-Hernandez RE et al (2012) Serum levels of macrophage migration inhibitory factor are associated with rheumatoid arthritis course. Rheumatol Int 32(8):2307–2311Google Scholar
  47. 47.
    Roger T, David J, Glauser MP, Calandra T (2001) MIF regulates innate immune responses through modulation of toll-like receptor 4. Nature 414(6866):920–924Google Scholar
  48. 48.
    Hong Z, Jiang Z, Liangxi W, Guofu D, Ping L, Yongling L, Wendong P, Minghai W (2004) Chloroquine protects mice from challenge with CpG ODN and LPS by decreasing proinflammatory cytokine release. Int Immunopharmacol 4(2):223–234Google Scholar
  49. 49.
    Meloni F, Solari N, Cavagna L et al (2009) Frequency of Th1, Th2 and Th17 producing T lymphocytes in bronchoalveolar lavage of patients with systemic sclerosis. Clin Exp Rheumatol 27(5):765–772Google Scholar
  50. 50.
    Yoshizaki A, Yanaba K, Iwata Y, Komura K, Ogawa A, Akiyama Y, Muroi E, Hara T, Ogawa F, Takenaka M, Shimizu K, Hasegawa M, Fujimoto M, Tedder TF, Sato S (2010) Cell adhesion molecules regulate fibrotic process via Th1/Th2/Th17 cell balance in a bleomycin-induced scleroderma model. J Immunol 185(4):2502–2515Google Scholar
  51. 51.
    Rodriguez-Reyna TS, Furuzawa-Carballeda J, Cabiedes J et al (2012) Th17 peripheral cells are increased in diffuse cutaneous systemic sclerosis compared with limited illness: a cross-sectional study. Rheumatol Int 32(9):2653–2660Google Scholar
  52. 52.
    O'Reilly S, Hugle T, van Laar JM (2012) T cells in systemic sclerosis: a reappraisal. Rheumatology 51(9):1540–1549Google Scholar
  53. 53.
    Rolla G, Fusaro E, Nicola S, Bucca C, Peroni C, Parisi S, Cassinis MC, Ferraris A, Angelino F, Heffler E, Boita M, Brussino L (2016) Th-17 cytokines and interstitial lung involvement in systemic sclerosis. J Breath Res 10(4):046013Google Scholar
  54. 54.
    Schmid AS, Hemmerle T, Pretto F, Kipar A, Neri D (2018) Antibody-based targeted delivery of interleukin-4 synergizes with dexamethasone for the reduction of inflammation in arthritis. Rheumatology 57(4):748–755Google Scholar
  55. 55.
    Bautista-Herrera LA, De la Cruz-Mosso U, Morales-Zambrano R et al (2018) Expression of MIF and TNFA in psoriatic arthritis: relationship with Th1/Th2/Th17 cytokine profiles and clinical variables. Clin Exp Med 18(2):229–235Google Scholar
  56. 56.
    De la Cruz-Mosso U, Garcia-Iglesias T, Bucala R et al (2018) MIF promotes a differential Th1/Th2/Th17 inflammatory response in human primary cell cultures: predominance of Th17 cytokine profile in PBMC from healthy subjects and increase of IL-6 and TNF-alpha in PBMC from active SLE patients. Cell Immunol 324:42–49Google Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2019

Authors and Affiliations

  • Christian Johana Baños-Hernández
    • 1
    • 2
  • José Eduardo Navarro-Zarza
    • 3
  • Richard Bucala
    • 4
  • Jorge Hernández-Bello
    • 1
    • 5
  • Isela Parra-Rojas
    • 2
  • María Guadalupe Ramírez-Dueñas
    • 6
  • Samuel García-Arellano
    • 1
    • 5
  • Luis Alexis Hernández-Palma
    • 1
  • Andrea Carolina Machado-Sulbarán
    • 6
  • José Francisco Muñoz-Valle
    • 1
    • 5
    Email author
  1. 1.Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la SaludUniversidad de GuadalajaraGuadalajaraMexico
  2. 2.Doctorado en Ciencias Biomédicas, Facultad de Ciencias Químico-BiológicasUniversidad Autónoma de GuerreroChilpancingo de los BravoMexico
  3. 3.Departamento de Medicina Interna-ReumatologíaHospital General de Chilpancingo “Dr. Raymundo Abarca Alarcón”Chilpancingo de los BravoMexico
  4. 4.Department of Medicine/Section of RheumatologyYale University School of MedicineNew HavenUSA
  5. 5.Instituto Transdisciplinar de Investigación y ServiciosUniversidad de GuadalajaraZapopanMexico
  6. 6.Laboratorio de Inmunología, Centro Universitario de Ciencias de la SaludUniversidad de GuadalajaraGuadalajaraMexico

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