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Protein kinase C (PKC) dependent induction of tissue factor (TF) by mesangial cells in response to inflammatory mediators and release during apoptosis
Author(s) -
Lang Detlef,
Terstesse Martin,
Dohle Frank,
Bangen Philip,
Banas Bernhard,
Pauels HansGerd,
Heidenreich Stefan
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704967
Subject(s) - protein kinase c , calphostin , tissue factor , calphostin c , mesangial cell , microbiology and biotechnology , proinflammatory cytokine , autocrine signalling , cytokine , signal transduction , tumor necrosis factor alpha , paracrine signalling , chemistry , protein kinase a , apoptosis , biology , inflammation , kinase , endocrinology , medicine , receptor , biochemistry , immunology , kidney , coagulation
In inflammatory kidney diseases procoagulatory activity (PCA) becomes evident. Glomerular fibrin deposits and capillary microthrombi are histopathological hallmarks in most forms of glomerulonephritis. Therefore in this study the expression of tissue factor (TF) as the main inducer of thrombogenesis was examined in cultured human mesangial cells (MC) in response to proinflammatory stimuli such as interleukin‐1 (IL‐1β), tumour necrosis factor alpha (TNF‐α) and lipopolysaccharide (LPS). Also main signalling pathways were investigated. IL‐1β, TNF‐α and LPS induced TF in MC in a time and dose dependent manner on mRNA and protein levels. Highest activity was found after 12 h of stimulation. Induction of TF was completely blockable by BAPTA‐AM, a chelator of intracellular [Ca 2+ ] i as well as calphostin, a protein kinase C (PKC) inhibitor. Activation of the protein kinase A (PKA) pathway had no influence on basal TF expression, but down‐regulated cytokine‐induced TF. The PKA blocker, KT5720, increased TF formation significantly. Since TF exerts its activity primarily on the surface of cells and after release of encrypted receptors we further tested TF activity in MC supernatants. IL‐1β did not significantly increase TF activity in supernatants of intact cells. However, when MC were rendered apoptotic by oxidative metabolites, IL‐1β treated MC released highly stimulated TF activity into the supernatants, suggesting that a paracrine activation of the coagulatory cascade can take place under such conditions. Inflammatory mediators up‐regulate TF expression in MC by a PKC dependent pathway whereas PKA can serve as a negative feed‐back link. Apoptosis of inflammatory MC may trigger to spread PCA.British Journal of Pharmacology (2002) 137 , 1116–1124. doi: 10.1038/sj.bjp.0704967