Activity, but not mRNA expression of gelatinases correlates with susceptibility to experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a model of multiple sclerosis (MS), inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). Clinically manifested EAE can be induced in Dark Agouti (DA) rats, but not in Albino Oxford (AO) rats by immunization with spinal cord homogenate (SCH) and complete Freund's adjuvant (CFA). Matrix metalloproteinases (MMP) play important roles in various steps of MS and EAE pathogenesis. Expression of gelatinases MMP2 and MMP9, their activator MMP14 and their inhibitor tissue inhibitor of MMP (TIMP)1 in the CNS of AO and DA rats immunized with SCH+CFA was determined. Expression of mRNA for MMP2, MMP9 and MMP14 was higher and expression of TIMP1 mRNA was lower in AO rats. However, gelatinase activity in spinal cords was higher in samples obtained from DA rats. Further, while there was no strain difference in MMP2 and MMP9 mRNA expression in lymph nodes of the immunized rats, gelatinase activity was higher in DA rats. This activity was reduced by antiinflammatory cytokines interleukin (IL)-10 and IL-4. Interestingly, gelatinase activity was detected in the nuclei of cells within the CNS, but not of those in lymph nodes. Our results imply that posttranscriptional regulation of MMP2 and MMP9 expression and/or function determines low gelatinase activity within the CNS and in immune cells of EAE-resistant AO rats.

Cell-type dependent response of melanoma cells to aloe emodin.

Intrinsic characteristics of melanoma cells such as expression of inducible nitric oxide synthase (iNOS), redox status, and activity of signaling pathways involved in proliferation, differentiation and cell death define the response of the cells to the diverse treatments. In this context we compared the effectiveness of herbal antaquinone aloe emodin (AE) against mouse B16 melanoma and human A375, different in initial activity of ERK1/2, constitutive iNOS expression and basal level of reactive oxygen species (ROS). Both cell lines are sensitive to AE treatment. However, while the agent induces differentiation of B16 cells toward melanocytes, in A375 cells promoted massive apoptosis. Differentiation of B16 cells, characterized by enhanced melanin production and tyrosinase activity, was mediated by H(2)O(2) production synchronized with rapid p53 accumulation and enhanced expression of cyclins D1 and D3. Caspase mediated apoptosis triggered in A375 cells was accompanied with Bcl-2 but not iNOS down-regulation. In addition, opposite regulation of Akt-ERK1/2 axis in AE treated B16 and A375 cells correlated with different outcome of the treatment. However, AE in a dose-dependent manner rescued both B16 and A375 cells from doxorubicin- or paclitaxel-induced killing. These data indicate that caution is warranted when AE is administrated to the patients with conventional chemotherapy.