Cross-talk between IL-6 and TGF-β signaling in hepatoma cells

AbstractInterleukin-6 (IL-6) is a multifunctional cytokine that plays important roles in the immune system, hematopoiesis, and acute phase reactions. Transforming growth factor-β (TGF-β) also has pleiotropy including the production of acute phase proteins in hepatocytes. To elucidate the cross-talk between IL-6 and TGF-β signaling pathways in hepatic cells, we investigated the effects of TGF-β on IL-6-induced signal transducer and activator of transcription-3 (STAT3) activation in a human hepatoma cell line, Hep3B. IL-6-induced activation of STAT3 activity and STAT3-mediated gene expression were augmented by TGF-β in Hep3B cells. We provide evidence that these activities were due to physical interactions between STAT3 and Sma- and MAD-related protein-3, bridged by p300. These results demonstrate a molecular mechanism of a cross-talk between STAT3 and TGF-β signaling pathways in hepatocytes

TGF-Β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia

金沢大学がん研究所がん幹細胞研究センターChronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase. It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells. Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML. Here, using a syngeneic transplantation system and a CML-like myeloproliferative disease mouse model, we show that Foxo3a has an essential role in the maintenance of CML LICs. We find that cells with nuclear localization of Foxo3a and decreased Akt phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a+/+ and Foxo3a-/- mice shows that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, we find that TGF-Β is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-Β inhibition, Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-Β inhibitor impaired their colony-forming ability in vitro. Our results demonstrate a critical role for the TGF-Β-FOXO pathway in the maintenance of LICs, and strengthen our understanding of the mechanisms that specifically maintain CML LICs in vivo. © 2010 Macmillan Publishers Limited. All rights reserved

Allergenic importance of 22 species of Japanese chironomid midges

Twenty-two Japanese chironomid species were examined for their allergenicities using ELISA with the sera of 32 asthmatic patients. The species Paratrichocladius rufiventris and Cricotopus sylvestris showed high positive rates of specific IgE, high average IgE reactivities and high frequencies of strong IgE reactivity and the highest IgE reactivity of the 22 species, suggesting a high rate of contact with humans and the possession of highly allergenic components by these two species. In contrast, Tanypus punctipennis and Rheotanytarsus kyotoensis showed low allergenicities, suggesting a low level of human contact and/or a lack of allergenic components. Furthermore, species that emerge from eutrophic waters in a large mass, such as Macropelopia paranebulosa, Paratrichocladius rufiventris and Chironomus yoshimatsui, showed strong allergenicities in all the tests. This suggests that eutrophic water be regarded as an important reservoir to allergenic chironomids