Although much promising data that interleukin (IL)-12 could be a powerful therapeutic agent against cancer were reported in animal models, its excessive toxicity has become a problem for its clinical application. IL-27 is a novel IL-12 family member that plays a role in the early regulation of T helper cell 1 initiation, including induction of T-bet and IL-12 receptor 2 expression. In the present study, we have evaluated the antitumor activity of IL-27 against a murine tumor model of colon carcinoma C26. C26 cells, which were transduced with the single-chain IL-27 cDNA and became secreting IL-27 (C26-IL-27), exhibited minimal tumor growth in vivo, and all of the mice inoculated with these cells survived healthily with complete tumor remission. Inoculation of mice with C26-IL-27 induced enhanced IFN-␥ production and cytotoxic T-lymphocyte activity against C26 tumor in spleen cells. Recovered mice from the inoculation showed a tumor-specific protective immunity to the following challenge with parental C26 tumor. The antitumor activity of IL-27 was almost diminished in nude mice, and depletion of CD8 ؉ T cells and neutralization of IFN-␥ in immunocompetent mice reduced greatly the antitumor activity. Moreover, the antitumor activity was abolished in T-bet-deficient mice, whereas it was observed unexpectedly in mice deficient of signal transducer and activator of transcription (STAT) 4. These results suggest that IL-27 has potent abilities to induce tumor-specific antitumor activity and protective immunity and that the antitumor activity is mediated mainly through CD8 ؉ T cells, IFN-␥, and T-bet but not through STAT4.
Complete laparoscopic anterior resection using NOSE does not require any incision and has excellent cosmetic properties, with mitigated postoperative pain.
Careful examination of liver, kidney or heart transplants in human recipients has revealed small numbers of host bone marrow derived stem cells in the graft. If the limited recipient repopulation of a donor graft that is currently observed could be facilitated, it is possible that conversion to a predominantly host phenotype would permit long term graft function without immunosuppression. We proposed to “engineer” repopulation after transplant in a strain combination (DA to Lewis GFP+) which rejects liver grafts strongly, a model which more closely resembles the situation in humans. Treatment on days 0,1,2,3 and 7 after transplantation with low-dose (0.1mg/kg) tacrolimus (T) designed to blunt rejection combined with plerixafor (P) to mobilize host stem cells resulted in greater than 180 day graft survival with extensive albeit spotty conversion of a small (50%) DA graft to the recipient Lewis GFP+ genotype. Subsequent skin grafting revealed donor specific graft prolongation. T plus P treatment resulted in higher levels of Lin-Thy1+CD34+CD133+ stem cells and Foxp3+ regulatory T cells in the blood and liver at day 7. Thus, pharmacological mobilization of host stem cells sustains liver allografts by two mechanisms: repopulation of injured donor cells, and regulation of the immune response.
IL-12 is a key immunoregulatory cytokine that promotes Th1 differentiation and cell-mediated immune responses. IL-12 stimulation results in the activation of Janus kinase 2 and tyrosine kinase 2 and, subsequently, STAT4 and STAT3. In addition, mitogen-activated protein kinase kinase 6/p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt pathways have been recently demonstrated to be activated by IL-12 and play an important role in IL-12 signaling. To further elucidate the molecular mechanism underlying IL-12 signaling, we have performed a yeast two-hybrid screening and identified mouse sphingosine kinase 2 (SPHK2) as a molecule associating with the mouse IL-12Rβ1 cytoplasmic region. Analyses of various mutants of each molecule revealed that the region including the proline-rich domain in SPHK2 is probably responsible for the binding to IL-12Rβ1, while the regions including the carboxyl terminus and Box II in the IL-12Rβ1 cytoplasmic region appear to be involved in the binding to SPHK2. Transient expression of wild-type SPHK2 in T cell hybridoma augmented IL-12-induced STAT4-mediated transcriptional activation. Ectopic expression of dominant-negative SPHK2 in Th1 cell clone significantly reduced IL-12-induced IFN-γ production, while that of wild-type SPHK2 enhanced it. In contrast, the expression minimally affected IL-12-induced proliferation. A similar decrease in IL-12-induced IFN-γ production was observed when dominant-negative SPHK2 was expressed in activated primary T cells using a retroviral expression system. These results suggest that SPHK2 associates with the IL-12Rβ1 cytoplasmic region and probably plays a role in modulating IL-12 signaling.
Emergency myelopoiesis is inflammation-induced hematopoiesis to replenish myeloid cells in the periphery, which is critical to control the infection with pathogens. Previously, pro-inflammatory cytokines such as interferon (IFN)-α and IFN-γ were demonstrated to play a critical role in the expansion of hematopoietic stem cells (HSCs) and myeloid progenitors, leading to production of mature myeloid cells, although their inhibitory effects on hematopoiesis were also reported. Therefore, the molecular mechanism of emergency myelopoiesis during infection remains incompletely understood. Here, we clarify that one of the interleukin (IL)-6/IL-12 family cytokines, IL-27, plays an important role in the emergency myelopoiesis. Among various types of hematopoietic cells in bone marrow, IL-27 predominantly and continuously promoted the expansion of only Lineage−Sca-1+c-Kit+ (LSK) cells, especially long-term repopulating HSCs and myeloid-restricted progenitor cells with long-term repopulating activity, and the differentiation into myeloid progenitors in synergy with stem cell factor. These progenitors expressed myeloid transcription factors such as Spi1, Gfi1, and Cebpa/b through activation of signal transducer and activator of transcription 1 and 3, and had enhanced potential to differentiate into migratory dendritic cells (DCs), neutrophils, and mast cells, and less so into macrophages, and basophils, but not into plasmacytoid DCs, conventional DCs, T cells, and B cells. Among various cytokines, IL-27 in synergy with the stem cell factor had the strongest ability to augment the expansion of LSK cells and their differentiation into myeloid progenitors retaining the LSK phenotype over a long period of time. The experiments using mice deficient for one of IL-27 receptor subunits, WSX-1, and IFN-γ revealed that the blood stage of malaria infection enhanced IL-27 expression through IFN-γ production, and the IL-27 then promoted the expansion of LSK cells, differentiating and mobilizing them into spleen, resulting in enhanced production of neutrophils to control the infection. Thus, IL-27 is one of the limited unique cytokines directly acting on HSCs to promote differentiation into myeloid progenitors during emergency myelopoiesis.
We investigated the hypothesis that a prominent effect of chronic ethanol consumption is mitochondrial DNA (mtDNA) injury and compared this injury in IL-6 knockout (KO) and wild-type (WT) mice. Ethanol feeding for 4 weeks resulted in steatosis and oxidative mtDNA damage (8-OHdG) in both IL-6KO and WT mice. However, the WT mice were able to repair the injury by increased production of mtDNA repair enzymes (OGG-1, Neil 1) and check point (p21, p53) proteins and avoid the mtDNA mutations. By contrast the IL-6 KO mice were unable to repair mtDNA resulting in deletions and diminished transcription of the mtDNA encoded protein cytochrome c oxidase subunit-I (COI). The mitochondrial injury was reflected by decreased membrane potential, reduced levels of ATP, and apoptosis-inducing factor (AIF)-induced apoptosis. Conclusion: IL-6 plays a critical role in allowing the liver to recover from significant mtDNA oxidation caused by alcohol. The data suggests that IL-6 activates mtDNA repair enzymes and induces cell cycle arrest allowing time for mtDNA repair. (HEPATOLOGY 2010;52:2137-2147
These findings indicate that CK20 is strongly related to lymph node metastasis and prognosis, suggesting its usefulness for the diagnosis of colorectal cancer recurrence. However, CK20 did not predict liver metastasis.
Abstract. Synchronous or metachronous liver metastasis occurs in approximately 15% of colorectal cancer patients and is an important negative prognostic factor. We therefore need an effective therapy to prevent metastasis. It has become apparent that cyclooxygenase (COX)-2 plays an important role in cancer growth, invasion and metastasis and that there is potential for chemoprevention via inhibition of these processes. We injected colon 26, a colorectal cancer cell line, in CDF1 mouse spleen and, from the following day, two kinds of COX-2 inhibitor (etodolac and nimesulide) were administered orally. Two weeks later, the animals were sacrificed, the liver was excised, and we counted the number of metastatic nodules on the liver surface. In addition, COX-2 mRNA, matrix metalloproteinase (MMP)-9 mRNA, and tissue inhibitor of MMP (TIMP)-1 mRNA of cancer tissue were measured by means of real-time RT-PCR. The number of metastatic nodules on the liver surface was significantly lower in the etodolac-treated group than in controls (p=0.001), but no significant difference was noted in the nimesulide-treated group. The expression of COX-2 mRNA was also significantly lower in the etodolactreated group than in controls (p=0.04), but not in the nimesulide-treated group. In addition, the expression of MMP-9 mRNA was significantly lower in the etodolac group than in controls (p=0.02), but not in the nimesulide group. Among the groups, there were no significant differences in TIMP-1 mRNA. Expression of COX-2 mRNA and MMP-9 mRNA correlated significantly (r=0.78, p=0.001), but there was no correlation between either COX-2 mRNA and TIMP-1 mRNA expression or between MMP-9 mRNA and TIMP-1 mRNA expression. These findings indicate that the selective COX-2 inhibitor, etodolac, suppresses liver metastasis by reducing MMP-9 activity.
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