Nuclear presence of nuclear factor of activated T cells (NFAT) c3 and c4 is required for Toll-like receptor-activated innate inflammatory response of monocytes/macrophages
| Autor: | Mike J. Shin, Kyung-Ok Kim, Saqib Nizami, Gook-Jin Chung, Ayse B. Celil Aydemir, Francis Y. Lee, Hiroshi Minematsu |
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| Rok vydání: | 2011 |
| Předmět: |
Lipopolysaccharides
Chromatin Immunoprecipitation NFATC3 Primary Cell Culture Biology Monocytes Article Lipopeptides Mice Bone Marrow Animals Humans RNA Messenger Cell Nucleus Mice Knockout Toll-like receptor Innate immune system NFATC Transcription Factors Tumor Necrosis Factor-alpha Macrophages Toll-Like Receptors NF-kappa B NFAT Cell Biology Acquired immune system Immunohistochemistry Molecular biology Immunity Innate TLR4 Cytokines Tumor necrosis factor alpha RNA Polymerase II Oligopeptides Signal Transduction |
| Zdroj: | Cellular Signalling. 23:1785-1793 |
| ISSN: | 0898-6568 |
| DOI: | 10.1016/j.cellsig.2011.06.013 |
| Popis: | Nuclear factor of activated T cells (NFATs) are crucial transcription factors that tightly control proinflammatory cytokine expression for adaptive immunity in T and B lymphocytes. However, little is known about the role of NFATs for innate immunity in macrophages. In this study, we report that NFAT is required for Toll-like receptor (TLR)-initiated innate immune responses in bone marrow-derived macrophages (BMMs). All TLR ligand stimulation including LPS, a TLR4 ligand, and Pam(3)CSK(4), a TLR1/2 ligand, induced expression of TNF which was inhibited by VIVIT, an NFAT-specific inhibitor peptide. BMMs from NFATc4 knock-out mouse expressed less TNF than wild type. Despite apparent association between NFAT and TNF, LPS did not directly activate NFAT based on NFAT-luciferase reporter assay, whereas NF-κB was inducibly activated by LPS. Instead, macrophage exhibited constitutive NFAT activity which was not increased by LPS and was decreased by VIVIT. Immunocytochemical examination of NFATc1-4 of BMMs exhibited nuclear localization of NFATc3/c4 regardless of LPS stimulation. LPS stimulation did not cause nuclear translocation of NFATc1/c2. Treatment with VIVIT resulted in nuclear export of NFATc3/c4 and inhibited TLR-activated TNF expression, suggesting that nuclear residence of NFATc is required for TLR-related innate immune response. Chromatin immunoprecipitation (ChIP) assay using anti-RNA polymerase II (PolII) antibody suggested that VIVIT decreased PolII binding to TNF gene locus, consistent with VIVIT inhibition of LPS-induced TNF mRNA expression. This study identifies a novel paradigm of innate immune regulation rendered by NFAT which is a well known family of adaptive immune regulatory proteins. |
| Databáze: | OpenAIRE |
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