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Protein Kinase C-Mediated Chemotaxis of Neutrophils Requires NF-B Activity but Is Independent of TNF Signaling in Mouse Skin In Vivo¹

Christophe Cataisson^*, Andrea J. Pearson^*, Sara Torgerson^*, Sergei A. Nedospasov and Stuart H. Yuspa^2,*

^* Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892; and Basic Research Program, SAIC-Frederick and Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702

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 PKC in the skin exhibit severe intraepidermal neutrophilic inflammation and keratinocyte apoptosis when treated topically with TPA. Activation of PKC increases the production of TNF and the transcription of chemotactic factors (MIP-2, KC, S100A8/A9), vascular endothelial growth factor, and GM-CSF in K5-PKC keratinocytes. In response to PKC activation, NF-B translocates to the nucleus and this is associated with IB phosphorylation and degradation. Preventing IB degradation reduces both the expression of inflammation-associated genes and chemoattractant release. To determine whether TNF mediated NF-B translocation and subsequent expression of proinflammatory factors, K5-PKC 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 TNF-neutralizing Abs. The in vivo treatment and TNFR deficiency did not prevent inflammation, and the in vitro treatment did not prevent NF-B nuclear translocation after TPA. Together these results implicate PKC as a regulator of a subset of cutaneous cytokines and chemokines responsible for intraepidermal inflammation independent of TNF. PKC inhibition may have therapeutic benefit in some human inflammatory skin disorders.

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