A PTP4A3 Peptide PIMAP39 Modulates TNF-Alpha Levels and Endotoxic Shock
| Autor: | Timothy Woodward, Xiaoren Tang, Salomon Amar |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Lipopolysaccharides
MAPK/ERK pathway Lipopolysaccharide medicine.medical_treatment p38 mitogen-activated protein kinases Stimulation Immediate-Early Proteins Mitogen-Activated Protein Kinase 14 Mice Structure-Activity Relationship chemistry.chemical_compound medicine Animals Humans Immunology and Allergy biology Tumor Necrosis Factor-alpha Nuclear Proteins Macrophage Activation Shock Septic Molecular biology Up-Regulation DNA-Binding Proteins Mice Inbred C57BL Cytokine chemistry Mitogen-activated protein kinase biology.protein Tumor necrosis factor alpha Protein Tyrosine Phosphatases Signal transduction Peptides Research Article Transcription Factors |
| Zdroj: | Journal of Innate Immunity. 2:43-55 |
| ISSN: | 1662-8128 1662-811X |
| DOI: | 10.1159/000235685 |
| Popis: | Lipopolysaccharide (LPS) stimulation of macrophages initiates intracellular signaling pathways leading to activation of MAPK and its subsequent influence on cytokine production. We recently identified a LITAF-STAT6(B) complex regulated by p38 MAPK in response to LPS stimulation. However, the LPS-induced cascade in the p38/LITAF/TNF signaling pathway remains unclear. Here, we identified PTP4A3, a protein tyrosine phosphotase, as a novel negative regulator of LPS-induced LITAF/TNF-alpha production. PTP4A3 exerts its negative role by dephosphorylating p38 alpha MAPK in response to LPS stimulation of primary macrophages. PTP4A3 expression is upregulated in primary macrophages. Further structure-function analysis revealed that a unique short peptide (PIMAP39) derived from PTP4A3 is capable of mimicking the functionality of full-length PTP4A3 to selectively dephosphorylate p38 alpha and indirectly suppress LPS-induced LITAF-STAT6B complex when it is translocated from the cytoplasmic region to the nucleus of the cell. Treatment of mice with PIMAP39 significantly attenuates the severity of adverse host responses to LPS stimulation, and in some cases provides complete resistance to a lethal dose of LPS due to suppression of TNF-alpha production. All together, these results reveal a previously unrecognized role for the PTP4A3 pathway in response to LPS. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|