CXCL10 EKSPRESYONUNUN DÜZENLENMESİ VE CXCL10 DNA DİZİ VARYASYONU VE HASTALIK İLİŞKİLERİNİN İNCELENMESİ
Öz
Amaç: Kemokin proteinlerinin, inflamasyon ve bağışıklıkta önemli rolleri vardır. Kemokinler, kemokin proteinleri ailesinin bir üyesi olup uygun kemokin reseptörlerini eksprese eden hücrelerde kemotaktik aktivite üreterek lökosit trafiğinde önemli bir rol oynarlar. CXCL10, CXC kemokin ailesinin bir üyesidir ve CXCR3 reseptörüne bağlanarak kemotaksi, apoptoz, hücre büyümesi, yeni damar oluşumu gibi biyolojik olaylarda etkili olur. CXCL10, otoimmün bozukluklar, transplantasyon, bulaşıcı hastalıklar ve kanser gibi farklı hastalık gruplarında etkileri olması dolayısıyla pleiotropiktir. Çalışmamızda CXCL10’un çeşitli hastalıkların patogenezi üzerindeki potansiyel rolünü değerlendirmek amaçlanmıştır. Gereç ve Yöntemler: CXCL10 ekspresyonunun eQTL etkileri ve mikroRNA’ların (miRNA’lar); birlikte düzenlenmiş gen kümeleri açısından düzenlenmesi incelendi. Gen-protein ve yolak etkileşimlerinin incelenmesi için STRING/GeneMANIA/KEGG PATHWAY/GeneCards; CXCL102’yi hedefleyen miRNA’ların tespiti için TargetScan/miRDB; CXCL10’u hedeflemek için Blood eQTL Tarayıcı / BIOS / mQTLdb; CXCL10 ve miRNA bölgesi tek nükleotid polimorfizmleri (SNP)’nin hastalıklarla olan ilişkisinin incelenmesi için GRASP ve GWAS, gen zenginleştirme analizi için ise GSEA/MSigDB veri tabanları kullanıldı. Bulgular: Birlikte eksprese edilen genler için, GSEA/MSigDB veri tabanında yapılan gen seti zenginleştirme analizi sonucunda, immün yanıt ve inflamatuar yanıtta yer alan genler, interferon ve düzenleyici T hücrelerine yanıtta yer alan genler, ve ayrıca meme ve prostat kanserlerinde yer alan genler ile gen setinin genişletilmesi önerildi (FDR<1E-50). CO-Düzenleme Veritabanı (CORD), CXCL10 çevresinde yer alan beş ek CXCL geni de dahil olmak üzere, yapısal olarak birlikte eksprese edilen 182 gen (5 kat eşikte) tanımladı. Birlikte eksprese edilen gen seti, herhangi bir miRNA’nın ortak hedefleri için zenginleşmeye sahip değildi. Çalışmamızda CXCL10’u hedefleyen miRNA’lar seçildi ve diğer hedef genleri belirlemek için de TargetScan programı kullanıldı. Böylece 80 miRNA belirlendi ve her bir miRNA’nın hedefleri aynı GSEA analizine tabi tutuldu. GWAS veri tabanlarındaki her bir miRNA gen bölgesi için SNP’lerin hastalıklar ile ilişkileri incelendi ve bu inceleme sonucunda Romatoid artrit, Ankilozan spondilit, Crohn Hastalığı, Psoriasis gibi otoimmün hastalıklar, Multipl Skleroz, Tip 1 diyabet, Miyastenia gravis ve alerji/astım gibi hastalıklar ile ilişki tespit edildi (P<1E- 04). CXCL10 içindeki SNP’ler için ise herhangi bir GWAS ilişkisi bulunmadı, ancak CXCL10 için kanda eQTL/meQTL olarak hareket eden SNP’lerin, uzun ömür, yaşlanma, inflamatuar barsak hastalığı (IBD) ve meme kanseri ile GWAS ilişkileri tespit edildi (P<1E-04). Çalışmamızda miRNA aracılı CXCL10 ekspresyonu için güçlü kanıtlar elde edilememiş olsa da, miRNA’ların yakınındaki varyantlar, inflamatuar ve immün bozukluklarla güçlü genetik ilişkiler gösterdi. Sonuç: CXCL10’un inflamasyon, otoimmünite ve muhtemelen kanserde oynadığı rolün transplantasyondan daha güçlü olduğu sonucuna vardık.
Anahtar Kelimeler
Genler hastalık ilişkileri otoimmün hastalıklar biyoinformatik CXCL10
Kaynakça
- 1. Gerber PA, Hippe A, Buhren BA, Muller A, Homey B. Chemokines in tumor-associated angiogenesis. Biol Chem 2009;390(12):1213-23. google scholar
- 2. Roccaro AM, Sacco A, Purschke WG, Moschetta M, Buchner K, Maasch C, et al. SDF-1 inhibition targets the bone marrow niche for cancer therapy. Cell Rep 2014;9(1):118-28. google scholar
- 3. Ciesielski CJ, Andreakos E, Foxwell BM, Feldmann M. TNFa-induced macrophage chemokine secretion is more dependent on NF-kB expression than lipopolysaccharides-induced macrophage chemokine secretion. Eur J Immunol 2002;32(7):2037-45. google scholar
- 4. Ohmori Y, Hamilton TA. The interferon-stimulated response element and a kB site mediate synergistic induction of murine IP-10 gene transcription by IFN-y and TNF-a. J Immunol 1995;154(10):5235-44. google scholar
- 5. Shields PL, Morland CM, Salmon M, Qin S, Hubscher SG, Adams DH. Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol 1999;163(11):6236-43. google scholar
- 6. Dillman JF 3rd, McGary KL, Schlager JJ. An inhibitor of p38 MAP kinase downregulates cytokine release induced by sulfur mustard exposure in human epidermal keratinocytes. Toxicol In Vitro 2004;18(5):593-9. google scholar
- 7. Ohmori Y, Hamilton TA. Cell type and stimulus specific regulation of chemokine gene expression. Biochem Biophys Res Commun 1994;198(2):590-6. google scholar
- 8. Treacy O, Ryan AE, Heinzl T, O’Flynn L, Cregg M, Wilk M et al. Adenoviral transduction of mesenchymal stem cells: in vitro responses and in vivo immune responses after cell transplantation. PLoS One 2012;7(8):e42662. doi: 10.1371/journal.pone.0042662. google scholar
- 9. Ahmadi Z, Arababadi MK, Hassanshahi G. CXCL10 activities, biological structure, and source along with its significant role played in pathophysiology of type I diabetes mellitus. Inflammation 2013;36(2):364-71. google scholar
- 10. Thelen M. Dancing to the tune of chemokines. Nat Immunol 2001;2(2):129-34. google scholar
- 11. Liu M, Guo S, Stiles JK. The emerging role of CXCL10 in cancer (Review). Oncol lett 2011;2(4):583-9. google scholar
- 12. Liu M, Guo S, Hibbert JM, Jain V, Singh N, Wilson NO et al. CXCL10/ IP-10 in infectious diseases pathogenesis and potential therapeutic implications. Cytokine Growth Factor Rev 2011;22(3):121-30. google scholar
- 13. Romagnani P, Crescioli C. CXCL10: candidate biomarker in transplantation. Clin Chin Acta 2012;413(17-18):1364-73. google scholar
- 14. Antonelli A, Ferrari SM, Giuggioli D, Ferrannini E, Ferri C, Fallahi P. Chemokine (C-X-C motif) ligand (CXCL)10 in autoimmune diseases. Autoimmun Rev 2014;13(3):272-80. google scholar
- 15. Moser M, Willimann K. Chemokines: role in inflammation and immune surveillance. Ann Rheum Dis 2004;63(Suppl 2):84-9. google scholar
- 16. Angiolillo AL, Sgadari C, Taub DD, Liao F, Farber JM, Maheshwari S, et al. Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med 1995;182(1):155-62. google scholar
- 17. Smit MJ, Verdijk P, van der Raaij-Helmer EM, Navis M, Hensbergen PJ, Leurs R, et al. CXCR3-mediated chemotaxis of human T cells is regulated by a Gi- and phospholipase C-dependent pathway and not via activation of MEK/p44/p42 MAPK nor Akt/PI-3 kinase. Blood 2003;102(6):1959-65. google scholar
- 18. Liu XF, Wang RQ, Hu B, Luo MC, Zeng QM, Zhou H, et al. MiR-15a contributes abnormal immune response in myasthenia gravis by targeting CXCL10. Clin Immunol 2016;164:106-13. google scholar
- 19. Liberzon A, Subramanian A Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov JP. Molecular Signatures database (MSigDB) 3.0. Bioinformatics 2011;27(12):1739-40. google scholar
- 20. Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Computational and Systems Biology Genetics and Genomics 2015;4:e05005. doi: 10.7554/eLife.05005. google scholar
REGULATION OF THE CXCL10 EXPRESSION AND INVESTIGATION OF THE RELATIONSHIPS OF THE CXCL10 DNA SEQUENCE VARIATION AND DISEASE
Öz
Objective: Chemokine proteins are significantly effective in inflammation and immunity. Chemokines are from the family of the chemokine proteins and they organise the leukocyte trafficking through the formation of chemotactic activity in the cells that express the appropriate chemokine receptors. CXCL10 is involved in the CXC chemokine family and is effective in biological events such as chemotaxis, apoptosis, cell growth, and angiostasis through the attachment to the CXCR3 receptor. CXCL10 is pleiotropic due to its effects on different disease groups such as autoimmune disorders, transplantation, infectious diseases, and cancer. The aim of this study was to assess the potential role of CXCL10 on the pathogenesis of various diseases. Material and methods: The eQTL effects of CXCL10 expression and the regulation of microRNAs (miRNAs) in terms of co-regulated gene clusters were examined. The STRING/GeneMANIA/KEGG PATHWAY/GeneCards was used for the investigation of the gene-protein and pathway interactions; for the detection of miRNA targeting CXCL102, TargetScan/ miRDB was used; for the investigation of the association of CXCL10 and miRNA region single nucleotide polymorphisms (SNP) with the diseases, GRASP and GWAS were used; GSEA/MSigDB database was used for gene enrichment analysis Results: Both the GSEA/MSigDB tool and the gene set enrichment analysis recommended the use of the enriched forms of the genes involved in breast and prostate cancers and in response to inflammation, and to interferon and regulatory T cells (FDR<1E-50). 182 genes (at a 5-fold threshold) that are structurally co-expressed with five additional CXCL genes close to CXCL10 were identified with the use of the CO-Regulation database (CORD. No enrichment was detected for the common targets of any miRNA in the co-expressed gene sets. The CXCL10 targeting miRNAs were selected, and the TargetScan program was used to identify other target genes in our study. Thus, 80 miRNAs were identified, and the same GSEA analysis was performed for each miRNA target. The association of SNPs with the diseases was investigated for the gene region of each miRNA in the GWAS databases, and an association was detected with the autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, and psoriasis, and with multiple sclerosis, Type 1 diabetes, myasthenia gravis, and allergy/asthma (P<1E-04). For SNPs in CXCL10, no GWAS associations were found; however, SNPs acting as eQTL/ meQTL in the blood for CXCL10 had GWAS associations with longevity, aging, inflammatory bowel disease (IBD), and breast cancer (P<1E-04). Although we found no strong evidence for miRNA-mediated CXCL10 expression in our study, strong genetic associations were found associated with inflammatory and immune disorders in the miRNAs neighboring variants. Conclusion: In conclusion, we suggest that there is a stronger role of CXCL10 in inflammation, autoimmunity, and possibly cancer than its role in transplantation.
Anahtar Kelimeler
Genes disease relationships autoimmune diseases bioinformatics CXCL10
Kaynakça
- 1. Gerber PA, Hippe A, Buhren BA, Muller A, Homey B. Chemokines in tumor-associated angiogenesis. Biol Chem 2009;390(12):1213-23. google scholar
- 2. Roccaro AM, Sacco A, Purschke WG, Moschetta M, Buchner K, Maasch C, et al. SDF-1 inhibition targets the bone marrow niche for cancer therapy. Cell Rep 2014;9(1):118-28. google scholar
- 3. Ciesielski CJ, Andreakos E, Foxwell BM, Feldmann M. TNFa-induced macrophage chemokine secretion is more dependent on NF-kB expression than lipopolysaccharides-induced macrophage chemokine secretion. Eur J Immunol 2002;32(7):2037-45. google scholar
- 4. Ohmori Y, Hamilton TA. The interferon-stimulated response element and a kB site mediate synergistic induction of murine IP-10 gene transcription by IFN-y and TNF-a. J Immunol 1995;154(10):5235-44. google scholar
- 5. Shields PL, Morland CM, Salmon M, Qin S, Hubscher SG, Adams DH. Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol 1999;163(11):6236-43. google scholar
- 6. Dillman JF 3rd, McGary KL, Schlager JJ. An inhibitor of p38 MAP kinase downregulates cytokine release induced by sulfur mustard exposure in human epidermal keratinocytes. Toxicol In Vitro 2004;18(5):593-9. google scholar
- 7. Ohmori Y, Hamilton TA. Cell type and stimulus specific regulation of chemokine gene expression. Biochem Biophys Res Commun 1994;198(2):590-6. google scholar
- 8. Treacy O, Ryan AE, Heinzl T, O’Flynn L, Cregg M, Wilk M et al. Adenoviral transduction of mesenchymal stem cells: in vitro responses and in vivo immune responses after cell transplantation. PLoS One 2012;7(8):e42662. doi: 10.1371/journal.pone.0042662. google scholar
- 9. Ahmadi Z, Arababadi MK, Hassanshahi G. CXCL10 activities, biological structure, and source along with its significant role played in pathophysiology of type I diabetes mellitus. Inflammation 2013;36(2):364-71. google scholar
- 10. Thelen M. Dancing to the tune of chemokines. Nat Immunol 2001;2(2):129-34. google scholar
- 11. Liu M, Guo S, Stiles JK. The emerging role of CXCL10 in cancer (Review). Oncol lett 2011;2(4):583-9. google scholar
- 12. Liu M, Guo S, Hibbert JM, Jain V, Singh N, Wilson NO et al. CXCL10/ IP-10 in infectious diseases pathogenesis and potential therapeutic implications. Cytokine Growth Factor Rev 2011;22(3):121-30. google scholar
- 13. Romagnani P, Crescioli C. CXCL10: candidate biomarker in transplantation. Clin Chin Acta 2012;413(17-18):1364-73. google scholar
- 14. Antonelli A, Ferrari SM, Giuggioli D, Ferrannini E, Ferri C, Fallahi P. Chemokine (C-X-C motif) ligand (CXCL)10 in autoimmune diseases. Autoimmun Rev 2014;13(3):272-80. google scholar
- 15. Moser M, Willimann K. Chemokines: role in inflammation and immune surveillance. Ann Rheum Dis 2004;63(Suppl 2):84-9. google scholar
- 16. Angiolillo AL, Sgadari C, Taub DD, Liao F, Farber JM, Maheshwari S, et al. Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med 1995;182(1):155-62. google scholar
- 17. Smit MJ, Verdijk P, van der Raaij-Helmer EM, Navis M, Hensbergen PJ, Leurs R, et al. CXCR3-mediated chemotaxis of human T cells is regulated by a Gi- and phospholipase C-dependent pathway and not via activation of MEK/p44/p42 MAPK nor Akt/PI-3 kinase. Blood 2003;102(6):1959-65. google scholar
- 18. Liu XF, Wang RQ, Hu B, Luo MC, Zeng QM, Zhou H, et al. MiR-15a contributes abnormal immune response in myasthenia gravis by targeting CXCL10. Clin Immunol 2016;164:106-13. google scholar
- 19. Liberzon A, Subramanian A Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov JP. Molecular Signatures database (MSigDB) 3.0. Bioinformatics 2011;27(12):1739-40. google scholar
- 20. Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Computational and Systems Biology Genetics and Genomics 2015;4:e05005. doi: 10.7554/eLife.05005. google scholar
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Klinik Tıp Bilimleri |
| Bölüm | Araştırma Makaleleri |
| Yazarlar | |
| Yayımlanma Tarihi | 28 Şubat 2023 |
| Gönderilme Tarihi | 25 Ekim 2022 |
| Yayımlandığı Sayı | Yıl 2023 Cilt: 6 Sayı: 1 |
