Apoptosis and inflammation generally exert opposite effects on tumorigenesis: apoptosis serves as a barrier to tumour initiation, whereas inflammation promotes tumorigenesis. Although both events are induced by various common stressors, relatively little is known about the stress-induced signalling pathways regulating these events in tumorigenesis. Here, we show that stress-activated MAP3Ks, ASK1 and ASK2, which are involved in cellular responses to various stressors such as reactive oxygen species, differentially regulate the initiation and promotion of tumorigenesis. ASK2 in cooperation with ASK1 functioned as a tumour suppressor by exerting proapoptotic activity in epithelial cells, which was consistent with the reduction in ASK2 expression in human cancer cells and tissues. In contrast, ASK1-dependent cytokine production in inflammatory cells promoted tumorigenesis. Our findings suggest that ASK1 and ASK2 are critically involved in tumorigenesis by differentially regulating apoptosis and inflammation.
Exquisitely regulated cytokine balance during early pregnancy is thought to be necessary for promoting survival of the fetal allograft. Our previous studies have demonstrated that membrane-bound human leukocyte antigen (mHLA-G) expressed on trophoblasts is one of the key factors in regulating cytokine balance by shifting the Th1/Th2 balance toward Th2 polarization, a favourable milieu for the maintenance of pregnancy. Given that trophoblasts secrete soluble HLA-G (sHLA-G), we examined its biological roles in comparison with mHLA-G. We cultured peripheral blood mononuclear cells (PBMC) with either the HLA-A and -B-deficient B lymphoblast cell line (721.221 cells) or the same cell line transfected with mHLA-G (721.221-G1 cells), in the presence or absence of recombinant sHLA-G. Cytokine concentrations in the culture media were determined by enzyme-linked immunosorbent assay. In contrast to mHLA-G protein, sHLA-G stimulated the release of tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, whereas it reduced the release of interleukin (IL)-3, regardless of the presence of the presence of a stimulatory effect of the mHLA-G-expressing cells. Although mHLA-G reduced the release of IL-4, sHLA-G did not have any effect. Conversely, sHLA-G stimulated the release of IL-10 whereas mHLA-G was without effect. These results suggest that sHLA-G regulates the release of cytokines from PBMC chiefly by counterbalancing mHLA-G, and thereby may play a role in maintaining pregnancy.
The attenuated expression of HLA-G protein on the extravillous trophoblasts could be at play in the pathophysiology of preeclampsia.
CD1d and CD1d-restricted natural killer T (NKT) cells serve as a natural bridge between innate and adaptive immune responses to microbes. CD1d downregulation is utilized by a variety of microbes to evade immune detection. We demonstrate here that CD1d is downregulated in human papillomavirus (HPV)-positive cells in vivo and in vitro.CD1d immunoreactivity was strong in HPV-negative normal cervical epithelium but absent in HPV16-positive CIN1 and HPV6-positive condyloma lesions. We used two cell lines for in vitro assay; one was stably CD1d-transfected cells established from an HPV-negative cervical cancer cell line, C33A (C33A/CD1d), and the other was normal human vaginal keratinocyte bearing endogenous CD1d (Vag). Flow cytometry revealed that cell surface CD1d was downregulated in both C33A/CD1d and Vag cells stably transfected with HPV6 E5 and HPV16 E5. Although the steady-state levels of CD1d protein decreased in both E5-expressing cell lines compared to empty retrovirus-infected cells, CD1d mRNA levels were not affected. Confocal microscopy demonstrated that residual CD1d was not trafficked to the E5-expressing cell surface but colocalized with E5 near the endoplasmic reticulum (ER). In the ER, E5 interacted with calnexin, an ER chaperone known to mediate folding of CD1d. CD1d protein levels were rescued by the proteasome inhibitor, MG132, indicating a role for proteasome-mediated degradation in HPV-associated CD1d downregulation. Taken together, our data suggest that E5 targets CD1d to the cytosolic proteolytic pathway by inhibiting calnexin-related CD1d trafficking. Finally, CD1d-mediated production of interleukin-12 from the C33A/CD1d cells was abrogated in both E5-expressing cell lines. Decreased CD1d expression in the presence of HPV E5 may help HPV-infected cells evade protective immunological surveillance.There are approximately 100 identified genotypes (types) of human papillomavirus (HPV). Over 40 of these are classified as genital HPV subtypes that invade the reproductive organs, including the uterine cervix, vaginal wall, vulva, and penis. Genital HPV types are further subclassified into high-risk types that are commonly associated with cervical cancer and low-risk types that cause noninvasive condyloma acuminata. Although exact classification varies among researchers, subtypes 16,18,31,33,35,39, 45, 51, 52, 56, 58, 66, and 68 are typically classified as high risk and subtypes 6,11,40,42,43,44, 54, 61, and 72 as low risk (44). Genital HPV infection involves short-term virus proliferation, followed by the long-term latent presence of a small number of copies of the viral genome within the basal cells of the genital epithelium (44). Infections with high-risk HPV subtypes result in progression to genital tract cancers (most commonly cervical) in only a small percentage of infected women and typically after a long latency period. A high percentage of high-risk HPV DNA-positive infected women resolve their infections during the proliferative phase and thereby clear the virus or progress to latency with...
Objective To determine the primary (&12 h) and secondary (12-24 h) effects of dexamethasone on fetal heart rate, short term heart rate variation, blood pressure, breathing movements and electrocortical activity, blood gas exchange, metabolism and adrenocortical function in the late gestation sheep fetus.Design Comparison of the effects of a single maternally administered intramuscular injection of dexamethasone (12 mg) with those of saline vehicle from 1 h before injection to 24 h post-injection. Fetal cardiovascular and behavioural parameters were recorded continuously. Fetal and maternal blood samples were taken at regular intervals for blood gas, glucose and lactate, cortisol and adrenocorticotrophin measurements.Sixteen chronically instrumented singleton fetal sheep at 127-133 days of gestation (term is about 147 days).During the primary phase short term heart rate variation fell (P < 0.001), and this was associated with a transient fall in the incidence of fetal breathing movements, a fall in fetal heart rate and a rise in fetal blood pressure. By 12 h there was a significant increase in short term heart rate variation (P < 0.001) and a rise in fetal heart rate, but blood pressure and fetal breathing movements had returned to normal. Dexamethasone significantly reduced fetal PaO, throughout most of the experimental period, particularly 1 h post-injection ( P < 0.005). Fetal and maternal plasma cortisol and adrenocorticotrophin concentrations fell significantly from 1 h post-injection.The effects of dexamethasone on fetal heart rate variation are more complex than previously described with both a fall and an increase observed depending on the t h e at which heart rate variation was measured after injection. Dexamethasone also caused a significant fall in fetal PaO,, and although this was not to hypoxic levels in normoxic fetuses it does raise questions about the potential impact of dexamethasone on chronically hypoxic fetuses. Sample
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