Identification of Secretory Leukoprotease Inhibitor As an Endogenous Negative Regulator in Allergic Effector Cells
نویسندگان
چکیده
Mast cells, basophils, and eosinophils are central effectors in allergic inflammatory disorders. These cells secrete abundant serine proteases as well as chemical mediators and cytokines; however, the expression profiles and functions of their endogenous inhibitors remain elusive. We found that murine secretory leukoprotease inhibitor (SLPI) is expressed in basophils and eosinophils but in not in mast cells. SLPI-deficient (Slpi-/-) basophils produce more cytokines than wild-type mice after IgE stimulation. Although the deletion of SLPI in basophils did not affect the release of chemical mediators upon IgE stimulation, the enzymatic activity of the serine protease tryptase was increased in Slpi-/- basophils. Mice transferred with Slpi-/- basophils were highly sensitive to IgE-mediated chronic allergic inflammation. Eosinophils lacking SLPI showed greater interleukin-6 secretion and invasive activity upon lipopolysaccharide stimulation, and the expression of matrix metalloproteinase-9 by these eosinophils was increased without stimulation. The absence of SLPI increases JNK1 phosphorylation at the steady state, and augments the serine phosphorylation of JNK1-downstream ETS transcriptional factor Elk-1 in eosinophils upon stimulation. Of note, SLPI interacts with a scaffold protein, JNK-interacting protein 3 (JIP3), that constitutively binds to the cytoplasmic domain of toll-like receptor (TLR) 4, suggesting that SLPI controls Elk-1 activation via binding to JIP3 in eosinophils. Mice transferred with Slpi-/- eosinophils showed the exacerbation of chitin-induced allergic inflammation. These findings showed that SLPI is a negative regulator in allergic effector cells and suggested a novel inhibitory role of SLPI in the TLR4 signaling pathways.
منابع مشابه
Protein Profiling of the Secretome of FcεRI Activated RBL-2H3.1 Cells
Background: Secretory proteins of IgE receptor activated mast cells and basophils play a pivotal role in the generation of immediate and long term immune responses in allergy and type I hypersensitivity. Objective: The present study aims to generate a 2-D map and profile of proteins secreted from a high secretory variant of the rat basophilic leukemia cell line, RBL-2H3.1, which in view of the ...
متن کاملEvaluate Toxocara Canis Excretory-Secretory Antigens in Experimental Allergic Encephalomyelitis (EAE)
BACKGROUND: Toxocara canis is the most prevalent intestinal roundworm of canid species. OBJECTIVES: This study aims to evaluate the effects of Toxocara canis excretory-secretory antigens (TcES Ag) on modulating the immune system in Experimental Allergic Encephalomyelitis (EAE) model. METHODS: Adult worms of T.canis were collected from dogs to obtain excretory-secretory antigens. Female C57BL/6m...
متن کاملIncreased Susceptibility to LPS-induced Endotoxin Shock in Secretory Leukoprotease Inhibitor (SLPI)-deficient Mice
Secretory leukoprotease inhibitor (SLPI) protects tissue against the destructive action of neutrophil elastase at the site of inflammation. Recent studies on new functions of SLPI have demonstrated that SLPI may play a larger role in innate immunity than merely as a protease inhibitor. To clarify the functions of SLPI in bacterial infections, we generated SLPI-deficient mice (SLPI(-/-) mice) an...
متن کاملMetalloproteinases Protects It from Cleavage by Matrix Secretory Leukoprotease Inhibitor and Surfactant Protein A Enhances Production of
متن کامل
Identification of Intracellular Sources Responsible for Endogenous Reactive Oxygen Species Formation
The endogenous reactive oxygen species ("ROS") formation is associated with many pathologic states such as inflammatory diseases, neurodegenerative diseases, brain and heart ischemic injuries, cancer, and aging. The purpose of this study was to investigate the endogenous sources for "ROS" formation in intact isolated rat hepatocytes, in particular, peroxisomal oxidases, monoamine oxidase, xanth...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 8 شماره
صفحات -
تاریخ انتشار 2017