RESUMEN
The interleukin-12 (IL-12) family is a class of heterodimeric cytokines that play crucial roles in pro-inflammatory and pro-stimulatory responses. Although some IL-12 and IL-23 paralogues have been found in fish, their functional activity in fish remains poorly understood. In this study, Pf_IL-12p35a/b, Pf_IL-23p19 and Pf_IL-12p40a/b/c genes were cloned from yellow catfish (Pelteobagrus fulvidraco), four α-helices were found in Pf_IL-12p35a/b and Pf_IL-23p19. The transcripts of these six genes were relatively high in mucus and immune tissues of healthy individuals, and in gill leukocytes. Following Edwardsiella ictaluri infection, Pf_IL-12p35a/b and Pf_IL-23p19 mRNAs were induced in brain and kidney (or head kidney), Pf_IL-12p40a mRNA was induced in gill, and Pf_IL-12p40b/c mRNAs were induced in brain and liver (or skin). The mRNA expression of these genes in PBLs was induced by phytohaemagglutinin (PHA) and polyinosinic-polycytidylic acid (poly I:C), while lipopolysaccharides (LPS) induced the mRNA expression of Pf_IL-12p35a and Pf_IL-12p40b/c in PBLs. After stimulation with recombinant (r) Pf_IL-12 and rPf_IL-23 subunit proteins, either alone or in combination, mRNA expression patterns of genes related to T helper cell development exhibited distinct differences. The results suggest that Pf_IL-12 and Pf_IL-23 subunits may play important roles in regulating immune responses to pathogens and T helper cell development.
Asunto(s)
Bagres , Infecciones por Enterobacteriaceae , Enfermedades de los Peces , Proteínas de Peces , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Inmunidad Innata , Subunidad p40 de la Interleucina-12 , Animales , Bagres/genética , Bagres/inmunología , Proteínas de Peces/genética , Proteínas de Peces/inmunología , Proteínas de Peces/química , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/veterinaria , Enfermedades de los Peces/inmunología , Regulación de la Expresión Génica/inmunología , Subunidad p40 de la Interleucina-12/genética , Subunidad p40 de la Interleucina-12/inmunología , Perfilación de la Expresión Génica/veterinaria , Inmunidad Innata/genética , Edwardsiella ictaluri/fisiología , Subunidad p35 de la Interleucina-12/genética , Subunidad p35 de la Interleucina-12/inmunología , Filogenia , Secuencia de Aminoácidos , Alineación de Secuencia/veterinaria , Subunidad p19 de la Interleucina-23/genética , Subunidad p19 de la Interleucina-23/inmunología , Poli I-C/farmacologíaRESUMEN
OBJECTIVES: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with an unsatisfactory state of treatment. We aim to explore novel targets for SLE from a genetic standpoint. METHODS: Cis-expression quantitative trait loci (eQTLs) for whole blood from 31,684 samples provided by the eQTLGen Consortium as well as two large SLE cohorts were utilized for screening and validating genes causally associated with SLE. Colocalization analysis was employed to further investigate whether changes in the expression of risk genes, as indicated by GWAS signals, influence the occurrence and development of SLE. Targets identified for drug development were evaluated for potential side effects using a phenome-wide association study (PheWAS). Based on the multiple databases, we explored the interactions between drugs and genes for drug prediction and the assessment of current medications. RESULTS: The analysis comprised 5427 druggable genes in total. The two-sample Mendelian randomization (MR) in the discovery phase identified 20 genes causally associated with SLE and validated 8 genes in the replication phase. Colocalization analysis ultimately identified five genes (BLK, HIST1H3H, HSPA1A, IL12A, NEU1) with PPH4 > 0.8. PheWAS further indicated that drugs acting on BLK and IL12A are less likely to have potential side effects, while HSPA1A and NEU1 were associated with other traits. Four genes (BLK, HSPA1A, IL12A, NEU1) have been targeted for drug development in autoimmune diseases and other conditions. CONCLUSIONS: .This study identified five genes as therapeutic targets for SLE. Repurposing and developing drugs targeting these genes is anticipated to improve the existing treatment state for SLE. Key Points ⢠We identified five gene targets of priority for the treatment of SLE, with BLK and IL12A indicating fewer side effects. ⢠Among the existing drugs that target these candidate genes, Ustekinumab, Ebdarokimab, and Briakinumab (targeting the IL12 gene) and CD24FC (targeting HSPA1A) may potentially be repurposed for the treatment of SLE.
Asunto(s)
Estudio de Asociación del Genoma Completo , Proteínas HSP70 de Choque Térmico , Lupus Eritematoso Sistémico , Análisis de la Aleatorización Mendeliana , Sitios de Carácter Cuantitativo , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/tratamiento farmacológico , Humanos , Proteínas HSP70 de Choque Térmico/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Subunidad p35 de la Interleucina-12/genética , Familia-src QuinasasRESUMEN
BACKGROUND/AIMS: Infection with hepatitis B virus (HBV) may result in various conditions. Natural course of HBV infection is influenced by various host immune factors and cytokines play a crucial role in host immune defense. This study was undertaken to investigate the association between HBV persistence and development of hepatocelluar carcinoma (HCC) and single nucleotide polymorphisms (SNPs) of interleukin (IL)-12A. METHODS: Between March 2002 and December 2004, seven hundred thirty Korean patients with HBV infection and 320 healthy individuals who recovered from HBV infection were enrolled. We assessed polymorphisms and haplotype in IL-12A, and the genotype distributions of the HBV clearance and persistence groups were compared in order to investigate the association between HBV persistence and SNPs of IL-12A. Moreover, the genotypic distributions between patients with HCC and without HCC were compared to investigate the association between the development of HCC and SNPs of IL-12A. RESULTS: We asssesed the SNPs of IL-12A at position +6400, +6624 and +7003. On the basis of logistic regression analysis, no statistically significant association with HBV persistence was observed with IL-12A exon 7 +6400, +6624, 3' UTR +7003 SNP and haplotype of IL-12A +6400/+6624/+7003. Furthermore, no statistically significant association of HCC development with IL-12A exon 7 +6400, +6624, 3' UTR +7003 SNP and haplotype of IL-12A +6400/+6624/+7003 was observed. CONCLUSIONS: These results suggest that SNPs and haplotype of IL-12A are not associated with HBV persistence and development of HCC. Further studies are needed to identify the host genetic factors in immune defense including cytokine gene polymorphisms of both IL-12A and IL-12B.