The expression of interleukin-12 is increased by MAP kinase phosphatase-1 through a mechanism related to interferon regulatory factor 1
| Autor: | Tiina Leppänen, Eeva Moilanen, Riku Korhonen, Tuija Hömmö, Noora Huotari |
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| Rok vydání: | 2012 |
| Předmět: |
MAPK/ERK pathway
Innate immune system Reverse Transcriptase Polymerase Chain Reaction Macrophages Immunology Blotting Western Dual Specificity Phosphatase 1 Enzyme-Linked Immunosorbent Assay Biology Interleukin-12 Cell biology Mice IRF1 Gene Knockdown Techniques MAP kinase phosphatase Interleukin 12 Gene silencing Animals Tumor necrosis factor alpha Protein kinase A Molecular Biology Interferon Regulatory Factor-1 |
| Zdroj: | Molecular immunology. 51(2) |
| ISSN: | 1872-9142 |
| Popis: | Mitogen-activated protein kinase phosphatase-1 (MKP-1) is a nuclear tyrosine/threonine phosphatase that inhibits p38 mitogen-activated protein kinase (MAPK) activity. We and others have shown that MKP-1 deficiency leads to excessive activation of innate immunity and inflammatory gene expression. Surprisingly, the present study shows that MKP-1 is a positive regulator of IL-12 expression in macrophages suggesting a stimulatory effect on Th1 type immune response. In the present study, we found that LPS-induced expression of IL-12p40 was lower in primary mouse peritoneal macrophages (PMs) and bone marrow-derived macrophages from MKP-1 deficient mice than in cells from wild-type mice whereas TNF expression was enhanced as expected. Correspondingly, the inhibition of p38 MAPK by pharmacologic inhibitors BIRB 796 and SB 202190 enhanced LPS-induced IL-12p40 production. Silencing of interferon regulatory factor 1 (IRF1) by siRNA inhibited the expression of IL-12p40 in J774 macrophages, showing that IRF1 is an important factor regulating IL-12p40 expression. BIRB 796 enhanced LPS-induced expression of IRF1 in J774 macrophages and in PMs from wild-type mice, and IRF1 expression was reduced in PMs from MKP-1 deficient mice. In conclusions, our results show that MKP-1 increases and p38 MAPK decreases the expression of IL-12 by enhancing the expression of IRF1. MKP-1, through regulation of IRF1 and IL-12, therefore may be an important factor supporting the development of Th1 type of immune response and anti-microbial defense. |
| Databáze: | OpenAIRE |
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