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1.
Cytokine Growth Factor Rev ; 25(2): 115-23, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24405806

ABSTRACT

Over the years, tumor necrosis factor (TNF) has been implicated in the pathogenesis of various inflammatory conditions and TNF antagonists are highly efficient in treatment of multiple autoimmune diseases. However, it has been shown that various cellular sources of TNF exhibit distinct and non-redundant functions that can be either deleterious or beneficial. This suggests that systemic TNF blockade, in addition to neutralization of pathogenic TNF, may abrogate its protective functions, resulting in adverse effects. Here we review the data on cellular sources of pathogenic and protective TNF and then discuss an experimental system based on humanized mice to study the role of cell-type specific TNF ablation during various disease models for development of cell-type specific TNF blockade.


Subject(s)
Autoimmune Diseases/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/immunology , Animals , Autoimmune Diseases/immunology , Inflammation/drug therapy , Inflammation/immunology , Lymphoid Tissue/immunology , Mice , Receptors, Tumor Necrosis Factor/immunology , Signal Transduction/immunology , Tumor Necrosis Factor-alpha/genetics
2.
Cancer Med ; 2(6): 815-25, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24403255

ABSTRACT

Interleukin 4 (IL-4) was shown to be tumor-promoting in full carcinogenesis studies using 3-methylcholanthrene (MCA). Because heretofore the role of IL-4 in DMBA/TPA (9,10-dimethyl-1,2-benz-anthracene/12-O-tetradecanoylphorbol-13-acetate) two-stage carcinogenesis was not studied, we performed such experiments using either IL-4(-/-) or IL-4Rα(-/-) mice. We found that IL-4Rα(-/-) but not IL-4(-/-) mice have enhanced papilloma formation, suggesting that IL-13 may be involved. Indeed, IL-13(-/-) mice developed more papillomas after exposure to DMBA/TPA than their heterozygous IL-13-competent littermate controls. However, when tested in a full carcinogenesis experiment, exposure of mice to 25 µg of MCA, both IL-13(-/-) and IL-13(+/-) mice led to the same incidence of tumors. While IL-4 enhances MCA carcinogenesis, it does not play a measurable role in our DMBA/TPA carcinogenesis experiments. Conversely, IL-13 does not affect MCA carcinogenesis but protects mice from DMBA/TPA carcinogenesis. One possible explanation is that IL-4 and IL-13, although they share a common IL-4Rα chain, regulate signaling in target cells differently by employing distinct JAK/STAT-mediated signaling pathways downstream of IL-13 or IL-4 receptor complexes, resulting in different inflammatory transcriptional programs. Taken together, our results indicate that the course of DMBA/TPA- and MCA-induced carcinogenesis is affected differently by IL-4 versus IL-13-mediated inflammatory cascades.


Subject(s)
Cytokines/genetics , Papilloma/genetics , Receptors, Cell Surface/genetics , Skin Neoplasms/genetics , 9,10-Dimethyl-1,2-benzanthracene , Animals , Carcinogens , Cytokines/blood , Interleukin-13 Receptor alpha1 Subunit/genetics , Methylcholanthrene , Mice , Mice, Inbred BALB C , Mice, Knockout , Papilloma/blood , Papilloma/chemically induced , Skin Neoplasms/blood , Skin Neoplasms/chemically induced , Tetradecanoylphorbol Acetate
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