IL-2 regulates the expression of the tumor suppressor IL-24 in melanoma cells.
ABSTRACT Melanoma is notoriously resistant to chemotherapy, but variable responses to biotherapies, including the IFNs and IL-2, provide intriguing avenues for further study. Systemic IL-2 treatment has provided significant clinical benefit in a minority of patients with metastatic melanoma, leading to long-term survival in a few cases. We hypothesize that one previously unidentified mechanism of effective IL-2 therapy is through direct upregulation of the tumor suppressor IL-24 in melanoma tumor cells resulting in growth suppression. In this study, five melanoma cell lines were treated with high dose recombinant human IL-2. Three (A375, WM1341, WM793) showed statistically significant increases in IL-24 protein; two (WM35, MeWo) remained negative for IL-24 message and protein. This increase was abolished by preincubating with anti-IL-2 antibody or blocking with antibodies against the IL-2 receptor chains. These IL-2 responsive melanoma cell lines expressed IL-2Rβ and IL-2Rγ mRNA. The IL-2Rβγ complex was functional, as measured by IL-2-induced signal transducers and activators of transcription activation as well as IL-15 signaling through its shared receptor complex. IL-24 upregulation was observed in response to either IL-2 or IL-15. Cell growth was significantly decreased by treatment of IL-24-positive cells with IL-2 or IL-15, whereas no effect was seen in negative cells. Incubating the IL-24 inducible-cells with anti-IL-24 antibody as well as transfecting with IL-24 small interfering RNA effectively reversed the growth suppression seen with IL-2. Thus, we have shown that one mechanism of clinically effective IL-2 therapy may be the direct action of IL-2 on a biologically distinct subset of melanoma cells leading to upregulation of the tumor suppressor IL-24.
Article: The efficacy of collagen dermis membrane and fibrin on cultured epidermal graft using an athymic mouse model.[show abstract] [hide abstract]
ABSTRACT: A human skin substitute consisting of human cultured keratinocytes, collagen dermis, and fibrin was evaluated in athymic mice. Eighty athymic mice were divided randomly into four groups. A 1.5x1.5-cm full-thickness wound defect was created on the back of each athymic mouse under anesthesia. These wounds were covered by sheets of cultured epidermal graft (group A), cultured epidermal graft with collagen dermis and fibrin (group B), cultured epidermal graft with collagen dermis (group C), or cultured epidermal graft with fibrin (group D). The grafts were secured and kept moist by specially designed saline gauze chambers. The take rates of the cultured graft with more than 50% of the wound covered were 65%, 15%, 50%, and 45% respectively. Group B had a significantly lower graft take rate, however the difference was not significant among groups A, C, and D. Light microscopy of biopsies of the grafted sites at 12 days showed complete epithelialization. The incidence of discharge from wound beds in groups A, B, C, and D was 0%, 15%, 15%, and 10% respectively. The results suggest that cultured cells are best grafted directly onto the wound bed or in combination with either a thin layer of collagen or fibrin but not both because the collagen dermal membrane and the fibrin together may impose too great a diffusion barrier for the cultured cell graft to become vascularized.Annals of Plastic Surgery 12/1999; 43(5):523-8. · 1.32 Impact Factor