Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05109 (S100A8)
 1,212 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase C (PKC) isoforms are major regulators of cutaneous homeostasis and mediate inflammation in response to 12-O-tetradecanoylphorbol-13-acetate (TPA). We have previously reported that transgenic mice overexpressing PKCalpha in the skin exhibit severe intraepidermal neutrophilic inflammation and keratinocyte apoptosis when treated topically with TPA. Activation of PKCalpha increases the production of TNFalpha and the transcription of chemotactic factors (MIP-2, KC, S100A8/A9), vascular endothelial growth factor, and GM-CSF in K5-PKCalpha keratinocytes. In response to PKCalpha activation, NF-kappaB translocates to the nucleus and this is associated with IkappaB phosphorylation and degradation. Preventing IkappaB degradation reduces both the expression of inflammation-associated genes and chemoattractant release. To determine whether TNFalpha mediated NF-kappaB translocation and subsequent expression of proinflammatory factors, K5-PKCalpha mice were treated systemically with a dimeric soluble form of p75 TNFR (etanercept) or crossed with mice deficient for both TNFR isoforms, and keratinocytes were cultured in the presence of TNFalpha-neutralizing Abs. The in vivo treatment and TNFR deficiency did not prevent inflammation, and the in vitro treatment did not prevent NF-kappaB nuclear translocation after TPA. Together these results implicate PKCalpha as a regulator of a subset of cutaneous cytokines and chemokines responsible for intraepidermal inflammation independent of TNFalpha. PKCalpha inhibition may have therapeutic benefit in some human inflammatory skin disorders.
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PMID:Protein kinase C alpha-mediated chemotaxis of neutrophils requires NF-kappa B activity but is independent of TNF alpha signaling in mouse skin in vivo. 1566 32

This study tested the hypothesis that human eosinophils produce ligands for the receptor for advanced glycation end-products (RAGE), express RAGE and exhibit RAGE-mediated responses. In examining our microarray data, we identified the presence of RAGE and RAGE ligand (S100A4, S100A6, S100A8, S100A9, S100A11, S100P, HMGB1) transcripts. Expression of eosinophil RAGE mRNA was also compared with a known positive control and further assessed via bioinformatics and sequence analysis of RAGE cDNA. Positive and negative controls were used to identify RAGE, S100A8 and S100A9 protein in human primary eosinophils. Immunoblot assessment of eosinophils treated with cytokines (IL-5 or granulocyte macrophage colony-stimulating factor) indicated an up-regulation of S100A8 and S100A9 production, whereas co-treatment of eosinophils with a RAGE ligand and cytokines displayed a down-regulation in the levels of RAGE. Analysis of eosinophil-conditioned media revealed that eosinophils are capable of releasing RAGE, S100A8 and S100A9. To test the eosinophil response to RAGE activation, the most well-characterized RAGE ligand, S100B, was examined. Treatment of eosinophils with S100B resulted in RAGE-mediated PKC-delta phosphorylation, a 3-fold dose-dependent increase in cell survival and an increase in the level of cellular RAGE. Combined, these studies reveal eosinophil expression of RAGE, RAGE ligands and RAGE-mediated responses. The expression of eosinophil RAGE, soluble RAGE and RAGE ligands may be pivotal to the functions of eosinophils in various human diseases involving RAGE and S100 ligands.
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PMID:Human eosinophils express RAGE, produce RAGE ligands, exhibit PKC-delta phosphorylation and enhanced viability in response to the RAGE ligand, S100B. 2202 32