title: CXCR2 ligands and G-CSF mediate PKCalpha-induced intraepidermal inflammation.
abstract: Transgenic mice overexpressing PKCalpha in the epidermis (K5-PKCalpha mice) exhibit an inducible severe intraepidermal neutrophilic inflammation and systemic neutrophilia when PKCalpha is activated by topical 12-O-tetradecanoylphorbol-13-acetate (TPA). This inducible model of cutaneous inflammation was used to define mediators of skin inflammation that may have clinical relevance. Activation of cutaneous PKCalpha increased the production of the chemotactic factors cytokine-induced neutrophil chemoattractant (KC) and macrophage inflammatory protein 2 (MIP-2) in murine plasma. TPA treatment of cultured K5-PKCalpha keratinocytes also released KC and MIP-2 into culture supernatants through an NF-kappaB-dependent pathway. MIP-2 and KC mediated the infiltration of neutrophils into the epidermis, since this was prevented by ablating CXCR2 in K5-PKCalpha mice or administering neutralizing antibodies against KC or MIP-2. The neutrophilia resulted from PKCalpha-mediated upregulation of cutaneous G-CSF released into the plasma independent of CXCR2. These responses could be inhibited by topical treatment with a PKCalpha-selective inhibitor. Inhibiting PKCalpha also reduced the basal and TNF-alpha- or TPA-induced expression of CXCL8 in cultured psoriatic keratinocytes, suggesting that PKCalpha activity may contribute to psoriatic inflammation. Thus, skin can be the source of circulating factors that have both local and systemic consequences, and these factors, their receptors, and possibly PKCalpha could be therapeutic targets for inhibition of cutaneous inflammation.
authors.affiliation: Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4255, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Cataisson
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Pearson
authors.forename: Margaret Z
authors.initials: MZ
authors.lastname: Tsien
authors.forename: Francesca
authors.initials: F
authors.lastname: Mascia
authors.forename: Ji-Liang
authors.initials: JL
authors.lastname: Gao
authors.forename: Saveria
authors.initials: S
authors.lastname: Pastore
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Yuspa
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000097:blood / Q000276:immunology; D019743:Chemokines, CXC / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003872:Dermatitis / Q000378:metabolism* / Q000473:pathology; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000906:Antibodies; C508606:CXCL8 protein, human; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D016209:Interleukin-8; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D051571:Protein Kinase C-alpha; D013755:Tetradecanoylphorbol Acetate