Interleukin-10 suppresses proliferation and remodeling of extracellular matrix of cultured human skin fibroblasts.

When we previously examined the participation of local expression of interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNFalpha) in wound healing of an intestinal anastomosis under septic conditions in mice, we found that IL-10 and TNFalpha expressions were markedly enhanced around the anastomosis and that wound healing was impaired in this animal model. The purpose of the present study was to investigate the combined effect of IL-10 on proliferation and remodeling of the extracellular matrix (ECM) of cultured human skin fibroblasts. Human skin fibroblasts were cultured for 48 h with IL-10 and/or TNFalpha at various concentrations, then the proliferation rates were determined using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The concentration of transforming growth factor-beta1 (TGFbeta1) in cell culture supernatants was measured by enzyme-linked immunosorbent assay, and type I collagen protein and matrix metalloproteinase-I (MMP-I) were detected by indirect immunofluorescence in cultured cells incubated for 48 h with 10 ng/ml of IL-10 and/or 10 ng/ml of TNFalpha. IL-10 itself had no effect on fibroblast proliferation, but reduced TNFalpha-induced fibroblast proliferation. The concentration of TGFbeta1 in cell culture supernatants was significantly lower in the presence of TNFalpha and IL-10 than in the presence of TNFalpha alone. Immunolabeling of fibroblasts for type I collagen protein was decreased in cells incubated with IL-10 and/or TNFalpha compared to controls. MMP-I immunolabeling was increased in cells incubated with IL-10, IL-10 and TNFalpha compared to control and cells incubated with TNFalpha. It is suggested that IL-10 is an inhibitory factor for the remodeling of the ECM during wound healing.

Effects of systemic and regional chemotherapy after hepatic resection for colorectal metastases.

BACKGROUND: Although the survival benefit of hepatic resection for colorectal metastasis has been established, some controversy remains regarding the significance of adjuvant chemotherapy after hepatic resection. METHODS: One hundred thirty-two consecutive patients who had liver resection for colorectal metastasis at our hospital between 1980 and 1997 were studied. After curative hepatic resection, 37 patients underwent systemic chemotherapy, administered orally or intravenously, and 38 patients underwent regional chemotherapy, given intra-arterially or intraportally. Forty patients had no adjuvant chemotherapy. The chemotherapeutic agents used for oral administration were uracil and Tegafur or Tegafur alone. Mitomycin C (MMC) or 5-FU was used for IV chemotherapy. Combinations of 5-FU/leucovorin or MMC/5-FU (doxorubicin) were used for regional chemotherapy. Univariate and multivariate analyses were applied to test the significance of adjuvant chemotherapy for patient survival or disease-free survival. RESULTS: Overall 5-year survival was 42.2% (95% CL: 31.2%, 53.2%). Among the possible prognostic factors studied, univariate analysis showed a significant difference in survival based on the number of tumors and lymph node metastases in the hepatic hilum. There was a significant difference in disease-free survival based on adjuvant chemotherapy and lymph node metastasis. The multivariate analysis for patient survival selected four prognostic factors (P < .05), including adjuvant chemotherapy, lymph node metastasis, disease-free interval, and tumor size. The multivariate analysis for disease-free survival selected adjuvant chemotherapy, lymph node metastasis, and disease-free interval as significant factors. The most common recurrence site was remnant liver, regardless of adjuvant chemotherapy. CONCLUSIONS: Adjuvant chemotherapy significantly improved survival and disease-free survival after hepatic resection for colorectal metastases. It did not decrease recurrence rate in the remnant liver.