Cytokine TGF-β1, TNF-α, IFN-γ and IL‐6 Gene Polymorphisms and Localization of Premalignant Gastric Lesions in Immunohistochemically H. pylori-negative Patients

Abstract Background Chronic inflammation with sustained unregulated immune stimulation in autoimmune rheumatic diseases (ARD) may be a risk factor for developing lymphoproliferative disorders (LPD). Markers of ARD activity as high erythrocyte sedimentation rate or erosive joint diseases and the development of B-symptoms were accounted as risk factors for LPD development. We investigated the association of five inflammatory cytokine genes single nucleotide polymorphisms (SNPs): TNF-α -308G>A; TGF-β1 gene codon 10 T>C and 25 G>C; IL-10 promoter SNPs -1082 A>G, -819T>C, and -592A>C; IL-6 -174G>C; and IFN-γ 874 T>A with the risk of LPD development in ARD patients. The study was conducted on 70 patients divided into group I, 25 ARD patients diagnosed as RA (n = 15) and SLE (n = 10) and with no history of malignancy; group II, 25 patients diagnosed with LPD and had no ARD; and group III, 20 patients diagnosed with both diseases: ARD and LPD. Cytokine genotyping was analyzed by PCR-sequence-specific primer (PCR-SSP). Results ARD+LPD patients had significantly higher frequency of TNF-α -308A allele and AA+AG genotype (high TNF-α producers) and IL-10 -1082A allele and AA genotype (low IL-10 producers) than ARD patients (p = 0.003, p = 0.024, p = 0.003, p = 0.03, respectively) with a significantly increased risk of LPD development in ARD patients expressing the corresponding alleles and genotypes. No significant differences were detected in the distribution frequency of either TGF-β1, IL-6, or IFN-γ SNPs between groups I and III or any of the studied SNPs between groups II and III. The distribution frequency of IL-10 ATA haplotype was significantly increased in group III as compared to group I (p = 0.037). Conclusion The significantly increased frequency of the high-TNF-α- and low-IL-10-producing alleles and genotypes in ARD patients may participate in the provision of a proinflammatory milieu that eventually increases the risk of LPD development.

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Γονιδιακή έκφραση και μελέτη παραγόντων που επηρεάζουν την πλαστικότητα των ανθρώπινων Τ βοηθητικών λεμφοκυττάρων σε μεταγγιζόμενους ασθενείς

10.12681/eadd/37037 ◽

2016 ◽

Author(s):

Παναγιώτα Σπαντιδέα

Keyword(s):

Cytometric Bead Array ◽

Tnf Α ◽

Ifn Γ ◽

Tgf Β1

Εισαγωγή: Ο πληθυσμός των CD4+ Τ κυττάρων είναι υπεύθυνος για την οργάνωση και ισορροπία του ανοσοποιητικού συστήματος και την αντιμετώπιση ειδικά έναντι σε κάθε αντιγόνο. Αυτό επιτυγχάνεται λόγω της πλαστικότητας των CD4+ κυττάρων μέσα (διαφοροποιούνται τα ρυθμιστικά Τ κύτταρα-Tregs) και κατά την έξοδό τους (παρθενικά CD4+ Τ κύτταρα) από τον θύμο καθώς και τα ερεθίσματα που δέχονται στο μικροπεριβάλλον τους κυρίως από αντιγόνα και κυτταροκίνες. Με τις αλλογενείς μεταγγίσεις αίματος (ABT) τεράστιος αριθμός αντιγόνων εισέρχεται στο σώμα του λήπτη και τον τροποποιεί με μηχανισμό ο οποίος δεν είναι πλήρως κατανοητός μέχρι σήμερα.Σκοπός της εργασίας: Στην παρούσα εργασία, μελετήθηκαν ο τρόπος και οι παράγοντες που επηρεάζουν την πλαστικότητα των CD4+ Τ κυττάρων υπό την επίδραση της μετάγγισης σε ασθενείς που είχαν υποβληθεί σε προγραμματισμένο χειρουργείο αρθροπλαστικής γόνατος ή ισχίου χωρίς άλλες ανοσοτροποποιητικές νόσους. Η διάκριση των ασθενών έγινε με βάση αν έλαβαν μετάγγιση (54 ασθενείς-group1) ή όχι (35 ασθενείς- group2).Ασθενείς, υλικά και μέθοδοι: Ηπαρινισμένα δείγματα ολικού αίματος από 89 ασθενείς συλλέχτηκαν πριν το χειρουργείο (BS) και αμέσως μετά το χειρουργείο μέχρι την πρώτη εβδομάδα (days 0-7) ή μέχρι το εξιτήριο, ένα μήνα μετά το χειρουργείο (1month) και κατά τον επανέλεγχο των ασθενών (>3months). Σε απομονωμένα PBMC’s ασθενών προσδιορίστηκε η μεταβολή των CD4+CD25high/+Foxp3+ (nTreg), CD4+CD25+CD127low/- (iTreg) και άλλων CD3+ πληθυσμών με την μέθοδο FACS και στο πλάσμα των ασθενών προσδιορίστηκαν οι συγκεντρώσεις των κυτταροκινών IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α, IFN-γ με την μέθοδο Cytometric Bead Array (CBA) και των υποδοχέων TNF-RI(p55/p60), TNF-RII(p75/p80), TGF-β1 και TGF-β2 την μέθοδο της ELISA. Επίσης πραγματοποιήθηκαν πειράματα λειτουργικότητας των Tregs σε δείγματα μεταγγισμένων και μη μεταγγισμένων ασθενών, μέσα στην πρώτη μετεγχειρητική εβδομάδα. Σε αυτά καλλιεργήθηκαν απομονωμένα Tregs και Teff από τον ίδιο ασθενή για 72 ώρες σε διάφορους λόγους παρουσία PHA και CFSE. Και τέλος, έγινε συσχέτιση της μετάγγισης με την σοβαρότητα των μετεγχειρητικών επιπλοκών και την παραμονή των ασθενών στο νοσοκομείο. Αποτελέσματα: Από τα παραπάνω πειράματα παρατηρήθηκε σημαντική αύξηση των CD4+CD25high/+Foxp3+ και CD4+CD25+CD127low/- μέχρι την πρώτη μετεγχειρητική εβδομάδα στους μεταγγισμένους αλλά όχι στους μη-μεταγγισμένους ασθενείς. Τα πειράματα λειτουργικότητας απέδειξαν ότι τα Tregs μεταγγισμένων και μη μεταγγισμένων ασθενών είναι λειτουργικά και ικανά να προκαλούν αναστολή του πολλαπλασιασμού των Teff, ωστόσο, τα Tregs των μεταγγισμένων ασθενών μπορούσαν να καταστέλλουν ισχυρότερα και παρουσία μεγαλύτερου αριθμού Teff στην καλλιέργεια. Από τις κυτταροκίνες που ανιχνεύτηκαν στο πλάσμα των ασθενών η IL-6, και οι υποδοχείς TNF-RI(p55/p60) και TNF-RII(p75/p80) εμφάνισαν σημαντική αύξηση ενώ σημαντική μείωση εμφάνισε ο TGF-β1 και ιδιαίτερο ρόλο φαίνεται να παίζουν οι IL-2 και TGF-β2. Παρατεταμένη νοσηλεία καθώς και αυξημένες και πιο σοβαρές μετεγχειρητικές επιπλοκές φαίνεται να εμφανίζουν οι μεταγγισμένοι ασθενείς συγκριτικά με τους μη-μεταγγισμένους.Συμπεράσματα: Οι ασθενείς που δέχονται μετάγγιση κατά την διάρκεια του χειρουργείου είναι ανοσοκατεσταλμένοι για τις πρώτες μέρες μετά την μετάγγιση και αυτό οφείλεται στον αυξημένο αριθμό των ρυθμιστικών τους κυττάρων και την επαγωγή των προφλεγμονωδών αποκρίσεων, έτσι οι ασθενείς αναπτύσσουν Th1 απόκριση και πολλαπλασιασμό των Tregs τα οποία καταστέλλουν τον πολλαπλασιασμό των Teff ισχυρότερα. Έτσι σταδιακά, τα Tregs καταστέλλουν τις προφλεγμονώδης αποκρίσεις μέχρι να επανέλθει η ισορροπία των ληπτών μετά την εγχείρηση. Ωστόσο, η ανοσοκαταστολή οφειλόμενη στην μετάγγιση που παρατηρείται τις πρώτες μέρες, οδηγεί τους ασθενείς σε παρατεταμένη νοσηλεία και αυξημένες μετεγχειρητικές επιπλοκές.

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PRODUCTION OF IL-10, TNF-α, IFN-γ, TGF-β1 BY DIFFERENT POPULATIONS OF ERYTHROID CELLS DERIVED FROM HUMAN EMBRYONAL LIVER

Cytokine ◽

10.1006/cyto.2001.0975 ◽

2002 ◽

Vol 17 (4) ◽

pp. 221-225 ◽

Cited By ~ 4

Author(s):

Serguei V. Sennikov ◽

Serguei V. Krysov ◽

Alexandr N. Silkov ◽

Tatiana V. Injelevskaya ◽

Vladimir A. Kozlov

Keyword(s):

Erythroid Cells ◽

Tnf Α ◽

Different Populations ◽

Ifn Γ ◽

Tgf Β1

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TGF-β1-mediated regulation of thymus and activation-regulated chemokine (TARC/CCL17) synthesis and secretion by HaCaT cells co-stimulated with TNF-α and IFN-γ

Journal of Dermatological Science ◽

10.1016/s0923-1811(02)00071-3 ◽

2002 ◽

Vol 30 (2) ◽

pp. 154-160 ◽

Cited By ~ 12

Author(s):

Xueyi Zheng ◽

Koichiro Nakamura ◽

Michiko Tojo ◽

Noritaka Oyama ◽

Akiko Nishibu ◽

...

Keyword(s):

Hacat Cells ◽

Tnf Α ◽

Ifn Γ ◽

Tgf Β1

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TNF-α − 308 G/A and IFN-γ + 874 A/T gene polymorphisms in Saudi patients with cutaneous leishmaniasis

BMC Medical Genetics ◽

10.1186/s12881-020-01043-9 ◽

2020 ◽

Vol 21 (1) ◽

Cited By ~ 3

Author(s):

Ahmed A. Ahmed ◽

Zafar Rasheed ◽

Tarek Salem ◽

Mohammed S. Al-Dhubaibi ◽

Ahmad A. Al Robaee ◽

...

Keyword(s):

Cutaneous Leishmaniasis ◽

Gene Polymorphisms ◽

Tnf Α ◽

Ifn Γ ◽

Saudi Patients

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Inflammatory and immunogenetic markers in correlation with pulmonary tuberculosis

Jornal Brasileiro de Pneumologia ◽

10.1590/s1806-37132013000600011 ◽

2013 ◽

Vol 39 (6) ◽

pp. 719-727 ◽

Cited By ~ 3

Author(s):

Beatriz Lima Alezio Muller ◽

Daniela Maria de Paula Ramalho ◽

Paula Fernanda Gonçalves dos Santos ◽

Eliene Denites Duarte Mesquita ◽

Afranio Lineu Kritski ◽

...

Keyword(s):

Inflammatory Response ◽

Pulmonary Tuberculosis ◽

Gene Polymorphisms ◽

Serum Levels ◽

Acute Inflammatory Response ◽

Reactive Protein ◽

Antituberculosis Treatment ◽

Tnf Α ◽

Referral Hospitals ◽

Ifn Γ

OBJECTIVE: To describe serum levels of the cytokines IL-10, TNF-α, and IFN-γ, as well as polymorphisms in the genes involved in their transcription, and their association with markers of the acute inflammatory response in patients with pulmonary tuberculosis.METHODS: This was a descriptive, longitudinal study involving 81 patients with pulmonary tuberculosis treated at two referral hospitals. We collected data on sociodemographic variables and evaluated bacteriological conversion at the eighth week of antituberculosis treatment, gene polymorphisms related to the cytokines studied, and serum levels of those cytokines, as well as those of C-reactive protein (CRP). We also determined the ESR and CD4+ counts.RESULTS: The median age of the patients was 43 years; 67 patients (82.7%) were male; and 8 patients (9.9%) were infected with HIV. The ESR was highest in the patients with high IFN-γ levels and low IL-10 levels. IFN-γ and TNF-α gene polymorphisms at positions +874 and −238, respectively, showed no correlations with the corresponding cytokine serum levels. Low IL-10 levels were associated with IL-10 gene polymorphisms at positions −592 and −819 (but not −1082). There was a negative association between bacteriological conversion at the eighth week of treatment and CRP levels.CONCLUSIONS: Our results suggest that genetic markers and markers of acute inflammatory response are useful in predicting the response to antituberculosis treatment.

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Study on Mechanism of Human Marrow Mesenchymal Stem Cell in Treating Patients with Aplastic Anemia.

Blood ◽

10.1182/blood.v110.11.4099.4099 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4099-4099

Author(s):

Zhenhua Qiao ◽

Xiujuan Zhao

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

T Cells ◽

Aplastic Anemia ◽

Hematopoietic Cell ◽

Control Group ◽

Rt Pcr ◽

Tnf Α ◽

Ifn Γ ◽

Tgf Β1

Abstract Objective: To explore mechanism of human marrow mesenchymal stem cells (MSCs) in treating patients with aplastic anemia(AA). Methods: MSCs in patients with aplastic anemia(AA) and the control group were separated with Percoll(1.073g/m L) and cultured in low glucose DMEM. Then, observed their morphologies,checked their molecule surface antigen by flow cytometry and examined the process of adipogenic differention. The mononuclear cells (MNC)of marrow in patients with AA were enriched based 1.077g/L density centrifuge and cultured in the 1640 medium. (1)MSC in control group and MNC in AA group were co-cultured with or without cytokines. The function of supporting hematopoiesis for MSC was to be observed in single confluence layer after plating by counting the total cells and the clones in every well every week. Then analyzed the dynamics of proliferation. T cells were harvested by using nylon column. MSC in control group and T cells in AA group were co-cultured. The proliferation of T cell was measured by MTT method. The CD25,CD69,CD4,CD8,Annexin-V expression rates of CD3+T cells were analyzed by flow cytometry .The gene and protein of IL-2, IL-4,IL-10,TNF-α,IFN-γ,TGF-β1 were examined by RT-PCR and ELISA respectively. MSC treated to the model of AA, by the examination of peripheral hemogram, bone marrow biopsy, pathological section of spleen. Results: There was no significant difference between control group MSC and AA-MSC in morphologies but adipogenic differentiation in AA patients is earlier than controls. The clones of CFU-GM in group(MSC)(78.46±3.58)/2×105 cells, after 14 days cultured was significantly higher than(9.21±4.32)/2×105 cells in group(CK + DMEM medium), while lower than (99.32±4.34)/2×105 cells in group(MSC+CK). (1)the Treg cells (TCD4+CD25+) in AA group (2.01±1.21)/ 2×105 was significantly lower than (4.43±1.67)/2×105 cells in control group, while(5.43±2.31) / 2×105 in group (MSC+AAT) was no more than (4.43±1.67)/2×105 cells in control group. (2) MSCs significantly inhibited T cell proliferation (P< 0. O5)by MTT. (3) RT-PCR and ELISA analysis showed that MSCs induced the expression of IL-4, IL-10, TGF-β1 and decreased significantly the expression of IL-2, TNF-α, IFN -γ in T cells of AA. the model of AA treated by MSCs showed improvements in 3 blood components greatly(p<0.05), Bone marrow proliferated and restored to the normal level, hematopoietic cell increased obviously (hematopoietic cell capacity was more than 40%), and atrophied spleen restore to normality. Conclusions: morphologies of AA’MSC had no evident different with the control but was more easy adipogenic differention. aplastic anemia belongs to autoimmune diseases in which T cells effect organ-specific destruction. The fundamental mechanism of MSC in treating AA should be potential to promote hematopoietic cell proliferation by adjusting immunity.

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Cytokine Gene Polymorphisms and Epstein-Barr Virus Infection after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v126.23.3125.3125 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3125-3125

Author(s):

Ren Lin ◽

Zhiping Fan ◽

Ke Zhao ◽

Qianli Jiang ◽

Jing Sun ◽

...

Keyword(s):

Epstein Barr Virus ◽

Post Transplant ◽

Barr Virus ◽

Ebv Infection ◽

Associated Diseases ◽

Tnf Α ◽

Cytokine Gene Polymorphisms ◽

Ifn Γ ◽

Epstein Barr ◽

Tgf Β1

Abstract Backgroud: Epstein-Barr virus (EBV) infection/reactivation and associated diseases remain common complications in recipients of HSCT, leading to severe end-organ diseases and malignance. Single nucleotide polymorphism (SNP) in cytokine genes is considered to be related with EBV-associated post-transplant lymphoproliferative disorders (PTLD) in solid-organ transplantation recipients. In this study, we analyzed the association between cytokine gene polymorphisms and EBV infection/reactivation or diseases in recipients undergoing allo-HSCT. Methods: A total of 233 patients who received allo-HSCT between March 2012 to December 2014 were enrolled in this study. Ten SNPs, including IL-1β -511 rs16944, IL-1RN +11100 rs315952, IL-2 -330 rs2069762, IL-4 -590 rs2243250, IL-10 -592 rs1800872, IL-12 +1188 rs3212227, TNF-α -308 rs1800629, TGF-β1-509 rs1800469, TGF-β1 +869 rs1800470, IFN-γ +874 rs2430561, were tested. The SNPs genotypes in patients with or without EBV infection/reactivation and associated diseases were compared. Besides, the risk factors for EBV infection/reactivation were studied. Results: Seventy-four patients developed EBV infection/reactivation. The patients with EBV infection/reactivation had higher frequencies of donor IL-1β -511 TT genotype, donor IL-4 -590 TT genotype and recipient TNF-α -308 GG genotype than those without (p=0.021, p=0.004, p=0.020, respectively) while the frequencies of donor IL-1β -511 CC genotype, donor IL-1RN +11100 TT genotype, donor IL-2 -330 TT genotype, donor IL-4 -590 CC genotype and recipient TNF-α-308 GA genotype in patients with EBV infection/reactivation were lower than those without (p=0.041, p=0.029, p=0.005, p=0.011, p=0.042, respectively). Multivariate analysis showed donor IL-4 -590TT genotype (p=0.016, HR=1.907, 95% CI =1.130-3.218) and recipient TNF-α -308GG genotype (p=0.002, HR=3.550, 95% CI=1.613-7.812) were risk factors for post-transplant EBV infection/reactivation while donor IL-1RN +11100TT genotype (p=0.001, HR=0.382, 95% CI=0.218-0.670) was protective factors for post-transplant EBV infection/reactivation. Twenty-one patients developed EBV-associated diseases. The patients who developed EBV-associated diseases had higher frequency of donor IFN-γ +874 AT genotype than those did not (p=0.027). On the contrary, the frequencies of donor IL-1β-511 CC genotype, donor IL-10 -592 AA genotype, donor IL-12 +1188 AA genotype and donor IFN-γ +874 AA genotype in patients with EBV-associated diseases were lower than those without (p=0.019, p=0.018, p=0.018, p=0.010, respectively). Conclusion: Several SNPs in cytokine genes might be associated with EBV infection/reactivation and the development of EBV-associated diseases in recipients of allo-HSCT. However, these association should be studied further. Disclosures No relevant conflicts of interest to declare.

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Coinfection with Enterohepatic Helicobacter Species Can Ameliorate or Promote Helicobacter pylori-Induced Gastric Pathology in C57BL/6 Mice

Infection and Immunity ◽

10.1128/iai.05357-11 ◽

2011 ◽

Vol 79 (10) ◽

pp. 3861-3871 ◽

Cited By ~ 33

Author(s):

Zhongming Ge ◽

Yan Feng ◽

Sureshkumar Muthupalani ◽

Laura Lemke Eurell ◽

Nancy S. Taylor ◽

...

Keyword(s):

Helicobacter Pylori ◽

Interleukin 17 ◽

Mrna Levels ◽

Cytokine Mrna ◽

Content Type ◽

Time Points ◽

Gastric Pathology ◽

Tnf Α ◽

Ifn Γ ◽

H Pylori

ABSTRACTTo investigate how different enterohepaticHelicobacterspecies (EHS) influenceHelicobacter pylorigastric pathology, C57BL/6 mice were infected withHelicobacter hepaticusorHelicobacter muridarum, followed byH. pyloriinfection 2 weeks later. Compared toH. pylori-infected mice, mice infected withH. muridarumandH. pylori(HmHp mice) developed significantly lower histopathologic activity index (HAI) scores (P< 0.0001) at 6 and 11 months postinoculation (MPI). However, mice infected withH. hepaticusandH. pylori(HhHp mice) developed more severe gastric pathology at 6 MPI (P= 0.01), with a HAI at 11 MPI (P= 0.8) similar to that ofH. pylori-infected mice.H. muridarum-mediated attenuation of gastritis in coinfected mice was associated with significant downregulation of proinflammatory Th1 (interlukin-1beta [Il-1β], gamma interferon [Ifn-γ], and tumor necrosis factor-alpha [Tnf-α]) cytokines at both time points and Th17 (Il-17A) cytokine mRNA levels at 6 MPI in murine stomachs compared to those ofH. pylori-infected mice (P< 0.01). Coinfection withH. hepaticusalso suppressedH. pylori-induced elevation of gastric Th1 cytokinesIfn-γandTnf-α(P< 0.0001) but increased Th17 cytokine mRNA levels (P= 0.028) at 6 MPI. Furthermore, mRNA levels ofIl-17Awere positively correlated with the severity of helicobacter-induced gastric pathology (HhHp>H. pylori>HmHp) (at 6 MPI,r2= 0.92,P< 0.0001; at 11 MPI,r2= 0.82,P< 0.002). Despite disparate effects on gastritis, colonization levels of gastricH. pyloriwere increased in HhHp mice (at 6 MPI) and HmHp mice (at both time points) compared to those in mono-H. pylori-infected mice. These data suggest that despite consistent downregulation of Th1 responses, EHS coinfection either attenuated or promoted the severity ofH. pylori-induced gastric pathology in C57BL/6 mice. This modulation was related to the variable effects of EHS on gastric interleukin 17 (IL-17) responses toH. pyloriinfection.

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