Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression

Autor: Sakurai, Daisuke, Zhao, Jian, Deng, Yun, Kelly, Jennifer A., Brown, Elizabeth E., Harley, John B., Bae, Sang Cheol, Alarcn-Riquelme, Marta E., Edberg, Jeffrey C., Kimberly, Robert P., Ramsey-Goldman, Rosalind, Petri, Michelle A., Reveille, John D., Vilá, Luis M., Alarcón, Graciela S., Kaufman, Kenneth M., Vyse, Timothy J., Jacob, Chaim O., Gaffney, Patrick M., Sivils, Kathy Moser, James, Judith A., Kamen, Diane L., Gilkeson, Gary S., Niewold, Timothy B., Merrill, Joan T., Scofield, R. Hal, Criswell, Lindsey A., Stevens, Anne M., Boackle, Susan A., Kim, Jae Hoon, Choi, Jiyoung, Pons-Estel, Bernardo A., Freedman, Barry I., Anaya, Juan Manuel, Martin, Javier, Yu, C. Yung, Chang, Deh Ming, Song, Yeong Wook, Langefeld, Carl D., Chen, Weiling, Grossman, Jennifer M., Cantor, Rita M., Hahn, Bevra H., Tsao, Betty P., Frostegård, Johan, Truedsson, Lennart, de Ramón, Enrique, Sabio, José M., Ortego-Centeno, Norberto, CAllejas, José Luis, González-Escribano, María F., Sánchez-Román, Julio, D'Alfonso, Sandra, Migliarese, Sergio, Sebastiani, Gian Domenico, Galeazzi, Mauro, Witte, Torsten, Lauwerys, Bernard R., Endreffy, Emoke, Kovács, László, Vasconcelos, Carlos, da Silva, Berta Martins, Scherbarth, Hugo R., Marino, Pilar C., Motta, Estela L., Gamron, Susana, Drenkard, Cristina, Menso, Emilia, Allievi, Alberto, Tate, Guillermo A., Presas, Jose L., Palatnik, Simon A., Abdala, Marcelo, Bearzotti, Mariela, Alvarellos, Alejandro, Caeiro, Francisco, Bertoli, Ana, Paira, Sergio, Roverano, Susana, Graf, Cesar E., Bertero, Estela, Caprarulo, Cesar, Buchanan, Griselda, Guillerón, Carolina, Grimaudo, Sebastian, Manni, Jorge, Catoggio, Luis J., Soriano, Enrique R., Santos, Carlos D., Prigione, Cristina, Ramos, Fernando A., Navarro, Sandra M., Berbotto, Guillermo A., Jorfen, Marisa, Romero, Elisa J., Garcia, Mercedes A., Marcos, Juan C., Marcos, Ana I., Perandones, Carlos E., Eimon, Alicia, Parque, Sanatorio, Battagliotti, Cristina G., Acevedo, Eduardo, Cucho, Mariano, de la Torre, Ignacio García, Ríos, Mario Cardiel, Moctezuma, José Francisco, Ceceña, Marco Maradiaga
Rok vydání: 2013
Předmět:
Cancer Research
medicine.medical_treatment
Genome-wide association study
Gene
Disease predisposition
0302 clinical medicine
Interleukin 10
immune system diseases
Lupus Erythematosus
Systemic
Disease activity
skin and connective tissue diseases
Genetics (clinical)
Regulation of gene expression
0303 health sciences
TGranscription factor Elk 1
Hispanic or Latino
Interleukin-10
Up-Regulation
3. Good health
Cytokine
Research Article
Protein Binding
Genotype
lcsh:QH426-470
Inmunología
Single-nucleotide polymorphism
Down regulation
Biology
Polymorphism
Single Nucleotide
White People
03 medical and health sciences
Asian People
Enfermedades autoinmunes
Lupus eritematoso sistémico
Genetics
medicine
Humans
Genetic Predisposition to Disease
Electrophoretic mobility shift assay
Gene cluster
Allele
Molecular Biology
Alleles
Ecology
Evolution
Behavior and Systematics
ets-Domain Protein Elk-1
030304 developmental biology
Lupus erythematosus
medicine.disease
Enfermedades
Introns
lcsh:Genetics
Binding affinity
Gene Expression Regulation
Haplotypes
Immunology
Controlled study
Genome-Wide Association Study
030215 immunology
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
PLoS Genetics, Vol 9, Iss 10, p e1003870 (2013)
Sakurai, D, Zhao, J, Deng, Y, Kelly, J A, Brown, E E, Harley, J B, Bae, S C, Alarcn-Riquelme, M E, Edberg, J C, Kimberly, R P, Ramsey-Goldman, R, Petri, M A, Reveille, J D, Vilá, L M, Alarcón, G S, Kaufman, K M, Vyse, T J, Jacob, C O, Gaffney, P M, Sivils, K M, James, J A, Kamen, D L, Gilkeson, G S, Niewold, T B, Merrill, J T, Scofield, R H, Criswell, L A, Stevens, A M, Boackle, S A, Kim, J H, Choi, J, Pons-Estel, B A, Freedman, B I, Anaya, J M, Martin, J, Yu, C Y, Chang, D M, Song, Y W, Langefeld, C D, Chen, W, Grossman, J M, Cantor, R M, Hahn, B H, Tsao, B P, Frostegård, J, Truedsson, L, de Ramón, E, Sabio, J M, Martin, J, Ortego-Centeno, N, CAllejas, J L, González-Escribano, M F, Sánchez-Román, J, D'Alfonso, S, Migliarese, S, Sebastiani, G D, Galeazzi, M, Witte, T, Lauwerys, B R, Endreffy, E, Kovács, L, Vasconcelos, C, da Silva, B M, Scherbarth, H R, Marino, P C, Motta, E L, Gamron, S, Drenkard, C, Menso, E, Allievi, A, Tate, G A, Presas, J L, Palatnik, S A, Abdala, M, Bearzotti, M, Alvarellos, A, Caeiro, F, Bertoli, A, Paira, S, Roverano, S, Graf, C E, Bertero, E, Caprarulo, C, Buchanan, G, Guillerón, C, Grimaudo, S, Manni, J, Catoggio, L J, Soriano, E R, Santos, C D, Prigione, C, Ramos, F A, Navarro, S M, Berbotto, G A, Jorfen, M, Romero, E J, Garcia, M A, Marcos, J C, Marcos, A I, Perandones, C E, Eimon, A, Parque, S, Battagliotti, C G, Acevedo, E, Cucho, M, de la Torre, I G, Ríos, M C, Moctezuma, J F, Ceceña, M M, Scherbarth, H R, Marino, P C, Motta, E L, Gamron, S, Drenkard, C, Menso, E, Allievi, A, Tate, G A, Presas, J L, Palatnik, S A, Abdala, M, Bearzotti, M, Alvarellos, A, Caeiro, F, Bertoli, A, Paira, S, Roverano, S, Graf, C E, Bertero, E, Caprarulo, C, Buchanan, G, Guillerón, C, Grimaudo, S, Manni, J, Catoggio, L J, Soriano, E R, Santos, C D, Prigione, C, Ramos, F A, Navarro, S M, Berbotto, G A, Jorfen, M, Romero, E J, Garcia, M A, Marcos, J C, Marcos, A I, Perandones, C E, Eimon, A & Battagliotti, C G 2013, ' Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression ', PL o S Genetics, vol. 9, no. 10, e1003870 . https://doi.org/10.1371/journal.pgen.1003870
Repositorio EdocUR-U. Rosario
Universidad del Rosario
instacron:Universidad del Rosario
PLoS Genetics
DOI: 10.1371/journal.pgen.1003870
Popis: Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.
Author Summary Systemic lupus erythematosus (SLE), a debilitating autoimmune disease characterized by the production of pathogenic autoantibodies, has a strong genetic basis. Variants of the IL10 gene, which encodes cytokine interleukin-10 (IL-10) with known function of promoting B cell hyperactivity and autoantibody production, are associated with SLE and other autoimmune diseases, and serum IL-10 levels are elevated in SLE patients correlating with increased disease activity. In this study, to discover SLE-predisposing causal variant(s), we assessed variants within the genomic region containing IL10 and its gene family member IL19, IL20 and IL24 for association with SLE in case and control subjects from diverse ancestries. We identified SLE-associated SNP rs3122605 located at 9.2 kb upstream of IL10 as the most likely causal variant in subjects of European ancestry. The SLE-risk allele of rs3122605 was dose-dependently associated with elevated IL10 expression at both mRNA and protein levels in peripheral blood samples from SLE patients and controls, which could be explained, at least in part, by its preferential binding to Elk-1, a transcription factor activated in B cells during active disease of SLE patients. Elk-1-mediated IL-10 overexpression could be downregulated by inhibiting activation of mitogen-activated protein kinases, suggesting a potential therapeutic target for SLE.
Databáze: OpenAIRE
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