SCH 47112, a novel staurosporine derivative, inhibits 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and epidermal hyperplasia in hairless mouse skin

Abstract

Protein kinase C (PKC) regulates keratinocyte growth and differentiation as well as inflammation in skin, processes which are abnormal in skin diseases such as psoriasis. 12-O-tetradecanoylphorbol-13-acetate (TPA) binds to and activates PKC. We investigated the effects of SCH 47112, a novel staurosporine derivative, which interacts with the catalytic domain of PKC, on TPA-induced inflammation and hyperplasia in hairless mouse skin and TPA-induced differentiation in cultured human keratinocytes. Dorsal mouse skin was treated with vehicle, TPA (2.0/ 2.5 nmol) or SCH 47112 followed by TPA. Epidermal thickness, and epidermal, upper dermal and deep dermal inflammation (assessed on an ordinal semiquantitative scale) were determined in biopsies taken 24 h and 48 h post-treatment. SCH 47112 (100 nmol) inhibited TPA-induced epidermal, upper dermal and deep dermal inflammation by 71%, 45% and 22%, respectively, at 24 h (n = 3, P < 0.05). TPA-induced epidermal hyperplasia was inhibited by SCH 47112 (400 nmol) by 38% at 48 h (n = 3, P < 0.05). In addition, in cultured human keratinocytes, SCH 47112 inhibited TPA induction of transglutaminase. I protein, which catalyzes the formation of crosslinked envelopes. These results indicate that SCH 47112 exhibits biological activity, inhibiting TPA-induced changes in hairless mouse skin in vivo and cultured human keratinocytes in vitro, and suggest that PKC inhibitors may have a therapeutic role in inflammatory skin diseases.

Comparative microarray analysis of gene expression during apoptosis-induction by growth factor deprivation or protein kinase C inhibition

“…A striking feature of the STS response was the activation of genes linked to in¯ammatory processes. It had been shown earlier that phorbol esters induce in¯ammation of the skin via activation of PKC ± a process which can be blocked by inhibition of PKC (Gupta et al, 1988;Reynolds et al, 1997). On the other hand our data indicate the induced expression of macrophage in¯ammatory protein 1 b (Mip1-b) and the related C10 protein.…”

Avarol inhibits TNF-α generation and NF-κB activation in human cells and in animal models

“…To evaluate the in vivo effect of avarol on skin, we selected the TPA- induced hyperplasia murine model. In this regard, there are some similarities between human psoriatic lesions and mouse skin following a topical application of TPA (Reynolds et al, 1997;Moriyama et al, 2004;Sato et al, 2004;Pittelkow, 2005). TPA induces biochemical and histopathological changes such as cell infiltration, edema, epidermal hyperplasia, production of pro-inflammatory cytokines, and activation of NF-κB pathway (Han et al, 2001;Afaq et al, 2005).…”

Antipsoriatic effects of avarol‐3′‐thiosalicylate are mediated by inhibition of TNF‐αgeneration and NF‐κB activation in mouse skin

“…The pathogenic mechanism of psoriasis is unclear, and good animal models do not yet exist. However, there are some similarities between human psoriatic lesions and mouse skin following a topical application of TPA (Reynolds et al , 1997; Moriyama et al , 2004; Sato et al , 2004; Pittelkow, 2005). TPA induces biochemical and histopathological changes in mouse skin, such as cell infiltration within the dermis and epidermis, oedema, epidermal hyperplasia, production of proinflammatory cytokines and chemokines and activation of the NF‐ κ B pathway (Han et al , 2001; Afaq et al , 2005).…”