IL‐12 as a therapeutic target for pharmacological modulation in immune‐mediated and inflammatory diseases: regulation of T helper 1/T helper 2 responses

Haskó, György; Szabó, Csaba

doi:10.1038/sj.bjp.0702689

Cited by 63 publications

(33 citation statements)

References 126 publications

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“…One strategy uses Th1 cytokines for enhancing immune responses to Th1 in order to inhibit the induction of Th2 responses in asthma. 32,33 IL-12 is the cardinal signal for the differentiation of Th1 lymphocytes, and considerable interest has been shown in possible utilization of its Th1-polarizing properties for treatment of Th2-driven pathologies, such as allergic asthma. In experimental animal models of asthma, administration of recombinant IL-12 during active sensitization transiently decreased the levels of IgG1 and IgE Abs and reduced IL-5 production, 34 and administration of IL-12 to actively sensitized mice, in which Th2-associated responses were established, suppressed recruitment of eosinophils to the airway.…”

Section: Discussionmentioning

confidence: 99%

A single administration of interleukin-4 antagonistic mutant DNA inhibits allergic airway inflammation in a mouse model of asthma

et al. 2003

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Interleukin 4 (IL-4) is essential for the switching of B cells to IgE antibody production and for the maturation of T helper (Th) cells toward the Th2 phenotype. These mechanisms are thought to play a crucial role in the pathogenesis of the allergic airway inflammation observed in asthma. In the present study, we examined the anti-inflammatory effects of DNA administration of murine IL-4 mutant Q116D/Y119D (IL-4 double mutant, IL-4DM), which binds to the IL-4 receptor a and is an antagonist for IL-4. Immunization of BALB/c mice with alum-adsorbed ovalbumin (OVA) followed by aspiration with aerosolized OVA resulted in the development of allergic airway inflammation. A single administration of IL-4DM DNA before the aerosolized OVA challenge protected the mice from the subsequent induction of allergic airway inflammation. Serum IgE level and extent of eosinophil infiltration in bronchoalveolar lavage (BAL) from IL-4DM DNA-administered mice were significantly lower than those in BAL from control plasmid-immunized mice. In our study, IL-4 or IL-4 mutants were not detected in sera from mice that had received a single administration of IL-4DM DNA. The results of this study provide evidence for the potential utility of IL-4 mutant antagonist DNA inoculation as an approach to gene therapy for asthma.

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Section: Discussionmentioning

confidence: 99%

A single administration of interleukin-4 antagonistic mutant DNA inhibits allergic airway inflammation in a mouse model of asthma

et al. 2003

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“…The significantly lower basal concentrations of IL-10 in the NF B-deficient mice are probably a result of the increased IL-12 (p40) concentrations, as these two cytokines have been shown to be reciprocally regulated, with increased concentrations of either one decreasing the concentrations of the other (Hasko & Szabo 1999). The decreased concentration of IL-10, however, seems to have no effect on the development of diabetes in these mice, even though IL-10 has been shown to be an important regulator of the development of diabetes (Wogensen et al 1994).…”

Section: Discussionmentioning

confidence: 99%

NFkappaB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes

Mabley¹,

Haskó²,

Liaudet³

et al. 2002

Journal of Endocrinology

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Insulin-dependent diabetes mellitus (IDDM) is a disease characterized by the autoimmune destruction of the pancreatic -cells, which requires the expression of a number of immune-related genes including major histocompatibility complex proteins, cytokines, chemokines, and cytotoxic enzymes, many of which are regulated by the transcription factor, NF B. Inhibition of the entire NF B family of transcription factors may be harmful, as these factors are involved in many normal physiological processes. However, identifying and targeting specific NF B subunits critical for the pathogenesis of disease may prove to be valuable in designing new therapeutic strategies. To assess the potential role of the NF B subunit, p50, in the development of IDDM, mice with gene disruption for NF B (p50) were investigated for susceptibility to IDDM. We found that p50-deficient mice were fully resistant against multiple low-dose streptozotocin-induced diabetes, a model of diabetes with a strong autoimmune component. The site of involvement of NF B (p50) lies at an early, critical juncture of immune activation and proinflammatory mediator production, because: (1) isolated islets of Langerhans from NF B (p50)-deficient mice were not protected from the islet dysfunction induced by in vitro application of proinflammatory cytokines; (2) p50-deficient mice were not resistant to diabetes induced by a single high dose of streptozotocin, a model with a large oxidant component and no autoimmune involvement; and (3) diabetes induced up-regulation of nitric oxide and interleukin-12 was blocked in the p50-deficient mice. Our data suggest that NF B (p50) has an essential role in the development of autoimmune diabetes. Selective therapeutic blockade of this subunit may be beneficial in preventing IDDM.

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“…IL-12 induces Th1 immune responses, and is thus linked with autoimmune diseases (40), while IL-23 is linked with autoimmune diseases via Th17 immune responses (41). IL-12 (42) and IL-23 (43,44) have also been reported to be involved in the pathogenesis of RA.…”

Section: Discussionmentioning

confidence: 99%

Decoy receptor 3 regulates the expression of various genes in rheumatoid arthritis synovial fibroblasts

Fukuda

Miura

Maeda

et al. 2013

International Journal of Molecular Medicine

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Abstract. Decoy receptor 3 (DcR3), a member of the tumor necrosis factor (TNF) receptor (TNFR) superfamily, lacks the transmembrane domain of conventional TNFRs in order to be a secreted protein. DcR3 competitively binds and inhibits members of the TNF family, including Fas ligand (FasL), LIGHT and TNF-like ligand 1A (TL1A). We previously reported that TNFα-induced DcR3 overexpression in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) protects cells from Fas-induced apoptosis. Previous studies have suggested that DcR3 acting as a ligand directly induces the differentiation of macrophages into osteoclasts. Furthermore, we reported that DcR3 induces very late antigen-4 (VLA-4) expression in THP-1 macrophages, inhibiting cycloheximideinduced apoptosis and that DcR3 binds to membrane-bound TL1A expressed on RA-FLS, resulting in the negative regulation of cell proliferation induced by inflammatory cytokines. In the current study, we used cDNA microarray to search for genes in RA-FLS whose expression was regulated by the ligation of DcR3. The experiments revealed the expression profiles of genes in RA-FLS regulated by DcR3. The profiles showed that among the 100 genes most significantly regulated by DcR3, 45 were upregulated and 55 were downregulated. The upregulated genes were associated with protein complex assembly, cell motility, regulation of transcription, cellular protein catabolic processes, cell membrane, nucleotide binding and glycosylation. The downregulated genes were associated with transcription regulator activity, RNA biosynthetic processes, cytoskeleton, zinc finger region, protein complex assembly, phosphate metabolic processes, mitochondrion, ion transport, nucleotide binding and cell fractionation. Further study of the genes detected in the current study may provide insight into the pathogenesis and treatment of rheumatoid arthritis by DcR3-TL1A signaling.

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IL‐12 as a therapeutic target for pharmacological modulation in immune‐mediated and inflammatory diseases: regulation of T helper 1/T helper 2 responses

Cited by 63 publications

References 126 publications

A single administration of interleukin-4 antagonistic mutant DNA inhibits allergic airway inflammation in a mouse model of asthma

A single administration of interleukin-4 antagonistic mutant DNA inhibits allergic airway inflammation in a mouse model of asthma

NFkappaB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes

Decoy receptor 3 regulates the expression of various genes in rheumatoid arthritis synovial fibroblasts

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