Dichloroacetate modulates cytokines toward T helper 1 function via induction of the interleukin-12–interferon-γ pathway

Abstract Interleukin 12 (IL-12) is a major inducer of interferon gamma (IFN-γ) and the principal mediator of T helper 1 (Th1) differentiation. To identify IL-12–regulated genes, which might contribute to Th1 differentiation and IFNG regulation, we employed microarray analysis. Surprisingly, a ubiquitously expressed proprotein convertase (PC), furin, was one of the most consistently IL-12–induced genes in T cells, and among PCs was the only one regulated by this cytokine. Furin was preferentially expressed in differentiated Th1 cells in a Stat4-dependent manner. Expression of furin enhanced IFN-γ secretion, whereas inhibition of furin interfered with IFN-γ production. Thus, we conclude that IL-12 induction of furin might represent a new aspect of IFN-γ regulation and control of Th1 differentiation.

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Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones.

Journal of Experimental Medicine ◽

10.1084/jem.179.4.1273 ◽

1994 ◽

Vol 179 (4) ◽

pp. 1273-1283 ◽

Cited By ~ 269

Author(s):

R Manetti ◽

F Gerosa ◽

M G Giudizi ◽

R Biagiotti ◽

P Parronchi ◽

...

Keyword(s):

T Cells ◽

Interferon Gamma ◽

Specific Antigen ◽

Th2 Cells ◽

Interleukin 12 ◽

T Helper ◽

Ifn Gamma ◽

Selection Of

Interleukin 12 (IL-12) facilitates the generation of a T helper type 1 (Th1) response, with high interferon gamma (IFN-gamma) production, while inhibiting the generation of IL-4-producing Th2 cells in polyclonal cultures of both human and murine T cells and in vivo in the mouse. In this study, we analyzed the effect of IL-12, present during cloning of human T cells, on the cytokine profile of the clones. The culture system used allows growth of clones from virtually every T cell, and thus excludes the possibility that selection of precommitted Th cell precursors plays a role in determining characteristics of the clones. IL-12 present during the cloning procedures endowed both CD4+ and CD8+ clones with the ability to produce IFN-gamma at levels severalfold higher than those observed in clones generated in the absence of IL-12. This priming was stable because the high levels of IFN-gamma production were maintained when the clones were cultured in the absence of IL-12 for 11 d. The CD4+ and some of the CD8+ clones produced variable amounts of IL-4. Unlike IFN-gamma, IL-4 production was not significantly different in clones generated in the presence or absence of IL-12. These data suggest that IL-12 primes the clone progenitors, inducing their differentiation to high IFN-gamma-producing clones. The suppression of IL-4-producing cells observed in polyclonally generated T cells in vivo and in vitro in the presence of IL-12 is not observed in this clonal model, suggesting that the suppression depends more on positive selection of non-IL-4-producing cells than on differentiation of individual clones. However, antigen-specific established Th2 clones that were unable to produce IFN-gamma with any other inducer did produce IFN-gamma at low but significant levels when stimulated with IL-12 in combination with specific antigen or insoluble anti-CD3 antibodies. This induction of IFN-gamma gene expression was transient, because culture of the established clones with IL-12 for up to 1 wk did not convert them into IFN-gamma producers when stimulated in the absence of IL-12. These results suggest that Th clones respond to IL-12 treatment either with a stable priming for IFN-gamma production or with only a transient low level expression of the IFN-gamma gene, depending on their stage of differentiation.

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Intranasal CpG-Oligodeoxynucleotide is a Potent Adjuvant of Vaccine against Helicobacter pylori, and T Helper 1 Type Response and Interferon-gamma Correlate with the Protection

Helicobacter ◽

10.1111/j.1523-5378.2005.00293.x ◽

2005 ◽

Vol 10 (1) ◽

pp. 71-79 ◽

Cited By ~ 34

Author(s):

Tong Shi ◽

Wen-zhong Liu ◽

Fei Gao ◽

Gui-ying Shi ◽

Shu-dong Xiao

Keyword(s):

Helicobacter Pylori ◽

Interferon Gamma ◽

T Helper ◽

T Helper 1 ◽

Cpg Oligodeoxynucleotide ◽

Type Response

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Pengaruh Simvastatin Terhadap Kadar Proliferasi Limfosit Mencit Balb/C yang Diinduce Sepsis dengan LPS

JAI (Jurnal Anestesiologi Indonesia) ◽

10.14710/jai.v5i3.6309 ◽

2013 ◽

Vol 5 (3) ◽

pp. 193

Author(s):

Made Ryan Kharmayani ◽

Haris Lutfi ◽

Danu Soesilowati

Keyword(s):

Interferon Gamma ◽

Adhesion Molecule ◽

Intercellular Adhesion Molecule ◽

T Helper ◽

Intercellular Adhesion Molecule 1 ◽

T Helper 1 ◽

Mhc Ii ◽

Leukocyte Function ◽

Post Test ◽

Coa Reductase

Latar Belakang : Statin, inhibitor 3-hidroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase merupakan agen yang paling efektif dalam menurunkan lipid dan mempunyai efek pleiotrofik yaitu anti inflamatori dan immunomodulatori. Statin juga memodifikasi interaksi interseluler dan kemotaksis seluler pada sistem imun serta berpotensi mempengaruhi limfosit T dengan cara menghambat iinteraksi antara adhesi molekul seluler leukocyte function-associated antigen-1 (LFA-1) dan intercellular adhesion molecule-1 (ICAM-1), juga menurunkan interferon gamma (IFN -ɣ) yang berperan dalam ekspresi class II major histocompatibilty complex (MHC II) pada antigen precenting cells (APC) dan merupakan proses penting dalam aktivasi sel T. Penurunan ekspresi MHC II berakibat pada inhibisi aktivasi CD 4 limfosit, sehingga mengakibatkan penurunan diferensiasi T helper-1 (Th1) dan pelepasan sitokin proinflamasi juga menurun.Tujuan : Membuktikan efek simvastatin dosis bertingkat peroral pada mencit yang diberi LPS intraperitoneal terhadap penurunan kadar proliferasi limfosit.Metode : Penelitian eksperimental laboratorik dengan desain randomized post test only controlled group pada 20 ekor mencit Balb/c yang disuntik lipopolisakarida 10 mg/KgBB intraperitoneal dan simvastatin dosis 0,03 mg, 0,06 mg dan 0,12 mg peroral. Mencit dibagi menjadi 4 kelompok secara random, yaitu K1 sebagai control, K2 yang mendapat simvastatin 0,03 mg, K3 yang mendapat simvastatin 0,06 mg dan K4 yang mendapat simvastatin 0,12 mg. Pemeriksaan limfosit diambil dari kultur limpa setelah 72 jam pemberian simvastatin. Uji statistik yang digunakan adalah parametrik ANOVA dan dilanjutkan PosterioriHasil : Kadar rerata limfosit kelompok K1 (1,546 ± 0,106), K2 (0,541 ± 0,046), K3 (0,471 ± 0,013) dan K4 (0,553 ± 0,02). Terdapat penurunan kadar limfosit secara signifikan pada kelompok K2, K3 dan K4 dibanding K1 dengan p <0,05. Tidak terdapat perbedaan bermakna antara kadar limfosit kelompok K2 dengan kelompok K3 dan K4 ( p>0,05) tetapi didapatkan perbedaan bermakna antara kelompok K3 dibandingkan kelompok K4 ( p<0,05).Simpulan : Simvastatin secara signifikan menurunkan kadar proliferasi limfosit pada mencit yang diberi LPS intraperitoneal. Dosis 0,06 mg memiliki efek menekan kadar proliferasi limfosit paling besar.

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