[Clinical analysis of fertility-sparing therapy of patients with complex atypical hyperplasia and endometrial cancer].

OBJECTIVE: To analyze the efficacy and prognosis of fertility-sparing therapy of the patient with complex atypical hyperplasia (CAH) and endometrial cancer (EC). METHODS: Clinical data of 191 EC and CAH patients who received fertility-sparing therapy in Peking University People's Hospital between January 2009 and September 2021 were recruited retrospectively. Outcomes of remission, recurrence and pregnancy were analyzed. RESULTS: (1) Efficacy and efficacy-related factors: The complete response (CR) rate was 86.1% (161/187) for all the patients, and the CR rate of the CAH patients were higher than that of the EC patients (92.7% vs. 79.1%, P=0.007), the CR rate was significant higher in the CAH patients (OR=2.786, P=0.035). (2) The recurrence rate was 19.3% (31/161), and the recurrence rate of the EC patients were much higher than that of the CAH patients (26.4% vs. 13.5%, P=0.039). The median recurrence time was 22.5 (9.0, 50.0) months. (3) The high risk factors of recurrence were pathological type of EC (χ2=4.880, P=0.027), without the use of metfor-min (χ2=7.075, P=0.008), longer time to complete remission (>7 months) (χ2=6.204, P=0.013), and no pregnancy (χ2=6.765, P=0.009). (4) Results of pregnancy and related factors: Among the patients who achieved CR, 108 patients had fertility willing with the pregnancy rate of 41.7% (45/108), and the live birth rate was 34.3% (37/108). The live birth rate was lower in EC than that in the CAH patients (28.6% vs. 42.4%, P=0.045). The median time to achieve pregnancy was 10.50 (5.75, 33.25) months. The pregnancy rate was significant higher in the patients with pregnancy history (OR=9.468, P < 0.001) and in those who received assisted reproductive therapy (OR=7.809, P < 0.001). CONCLUSION: Fertility-sparing therapy of CAH and EC patients is effective resulting in high disease remission and certain pregnancy. However, the high recurrence rate and low pregnancy rate are still key problems for EC and CAH patients, therefore close monitoring and follow-up are indicated.

Clinical impacts of sun exposures on the faces and hands of Japanese women of different ages.

OBJECTIVE: To assess the impacts of sun exposures on some skin signs on the faces and hands of differently aged Japanese women, according to their distinct behaviours towards vis à vis sun exposure. METHODS: Two comparable cohorts of Japanese women (aged 18-83 years) were created according to their usual behaviour towards sun exposure i.e. non-sun-phobic (N = 495) and sun-phobic (N = 516) and through their regular use(s) of a photo-protective product. Standard photographs (full-face and 45° lateral) allowed to focus on 18 facial signs that were graded by 15 experts, using a referential skin ageing Atlas. From these two cohorts, two sub-cohorts (114 and 122 women) were created with regard to the similar clinical aspects of the dorsal side of their hands (Left vs. Right) that were further graded. Absolute differences in the scores of each sign were used (non-sun-phobic minus sun-phobic), by age-ranges, to better ascertain the impact of sun exposures and photo-protection. RESULTS: Facial signs related to skin wrinkles/texture and pigmentary spots were found significantly more accentuated among non-sun-phobic women and show an early onset (20-30 years). Facial sagging and crow's feet wrinkles appear delayed (30-40 years). The severity of vascular disorders was found to be similar in the two cohorts. The absolute differences in the grading's of almost all signs were unsurprisingly found increased with advancing ages, illustrating the combination of chronological and photo-ageing processes. With regard to hands, differences in skin texture and pigmentary disorders are of a late onset (40-50 years) and were found much increased at older ages. The cutaneous signs of the hands of Japanese women can hardly be taken as reliable markers of their photo-ageing status. CONCLUSION: The present work illustrates, for the first time, some specificities of the impact of sun exposures on the facial skin of Japanese women, pinpointing the fact that some facial signs are of an early onset. Results significantly confirm the importance of both sun avoidance coupled with photo-protective measures.

OBJECTIF: D'évaluer les impacts de l'exposition solaire sur plusieurs signes du visage et des mains de femmes Japonaises d'âge différents, selon leurs différents comportements vis-à-vis de l'exposition solaire. MÉTHODES: Deux cohortes comparables de femmes Japonaises (âgées de 18 à 83 ans) ont été créées selon leur comportement habituel vis à vis de l'exposition solaire, phobique (N = 516) ou non (N = 495) et selon leur utilisation(s) régulière(s) de produits photo-protecteurs. Des photographies standardisées du visage de face et latérales (45°) ont permis de se focaliser sur 18 signes cliniques du visage dont la sévérité a été quantifiée par 15 experts, utilisant un Atlas de référence du vieillissement cutané. De ces deux cohortes, deux sous-cohortes ont été extraites (114 et 122 femmes) par les aspects cliniques similaires de la face dorsale de leurs mains (Gauche vs. Droite) pour être ensuite quantifiées. Les différences absolues de chaque signe (non-phobiques moins phobiques), par tranches d'âges, ont été utilisées pour mieux déterminer l'impact des expositions solaires et des routines de photo-protection. RÉSULTATS: Les signes du visage liés à la texture cutanée/rides et aux taches pigmentaires ont été trouvés significativement aggravés chez les femmes non-phobiques de l'exposition solaire et d'apparition précoce (20-30 ans) tandis que la ptose du visage ou les rides de la patte d'oie apparaissent plus tardivement (30-40 ans). La sévérité des désordres vasculaires du visage a été trouvée similaire dans les deux cohortes. Les différences absolues dans la sévérité de la plupart des signes ont été logiquement trouvées accrues avec l'âge, illustrant la combinaison du vieillissement chronologique et de celui photo-induit. Concernant les mains, les différences dans la texture cutanée et les désordres pigmentaires apparaissent significativement tardives (40-50 ans) et augmentent à des âges plus avancés. Les signes cutanés des mains des femmes Japonaises ne semblent donc pas être des marqueurs fiables du vieillissement photo-induit. CONCLUSION: La présente étude illustre, pour la première fois, quelques spécificités des impacts de l'exposition solaire sur les signes faciaux de femmes Japonaises, pointant le fait que certains sont d'apparition précoce. Les résultats confirment de manière significative l'importance d'éviter les expositions solaires et de recourir à des mesures photo-protectrices.

Hypoxia-inducible factor-1α inhibits interleukin-6 and -8 production in gingival epithelial cells during hypoxia.

BACKGROUND AND OBJECTIVE: Hypoxia has been widely studied in inflammatory diseases as it can modulate the inflammatory response, mainly via the hypoxia-inducible factor (HIF). However, little is known about the effects of hypoxia and the role of HIF in the inflammatory responses to periodontitis. In this study, we focused on the gingival epithelium that is exposed to relatively low levels of oxygen. We investigated whether hypoxic conditions have an impact on inflammatory responses in human gingival epithelial cells (HGECs). MATERIAL AND METHODS: Pimonidazole HCl, which accumulates in hypoxic cells, was administered intraperitoneally to C57BL/6 mice with or without Porphyromonas gingivalis infection. Immunohistochemistry was then performed to detect the hypoxic cells in periodontal tissue. Immortalized HGECs were cultured under hypoxic conditions with or without interleukin (IL)-1ß, and the expression levels of IL-6 and IL-8 were measured by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. HIF-1α expression was detected by western blotting. The DNA-binding activity of HIF-1α was determined by a DNA-binding enzyme-linked immunosorbent assay. The involvement of HIF-1α in the hypoxic response was examined by transfection with HIF-1α siRNA. RESULTS: Immunohistochemistry revealed pimonidazole HCl accumulation in the gingival epithelium of both normal and P. gingivalis-infected mice, with a slightly stronger signal in the P. gingivalis-infected mice than in the normal mice. The IL-1ß-induced IL-6 and IL-8 production by HGECs was suppressed under hypoxic conditions. HIF-1α accumulated during hypoxia, and this accumulation was further enhanced by IL-1ß treatment. The hypoxia-dependent suppression of IL-6 and IL-8 expression was reversed by treating the cells with HIF-1α siRNA. CONCLUSION: Our results suggest that the gingival epithelium is exposed to low oxygen tension in periodontal tissue and that this hypoxic condition modulates the local inflammatory response of gingival epithelial cells in an HIF-1α-dependent manner.

Evaluation of the global DNA methylation in canine mast cell tumour samples by immunostaining of 5-methyl cytosine.

Cutaneous mast cell tumours (MCT) are the most common skin tumour in dogs, and to our knowledge, there are no previous studies regarding the global methylation of these tumours. DNA hypomethylation and hypermethylation have been described in several tumours and both mechanisms can lead to carcinogenesis. The purpose of this study was to evaluate the global DNA methylation in canine MCT. A total of 48 MCT samples were classified in grades 1, 2 and 3 or high-grade or low-grade. Monoclonal antibodies were used for the immunohistochemical detection of the 5-methylcytosine. The immunostained nuclei were classified in strong, weak or negative pattern, and these were quantified in five distinct microscopic fields (40× objective) in each slide. The results showed that global DNA hypomethylation was predominant in grade 3, high-grade, less differentiated MCT. These epigenetic changes in neoplastic mast cells warrant further detailed investigation aiming the establishment of tumour epigenetic therapies.

Regulation of somatostatin receptor 4-mediated cytostatic effects by CD26 in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from mesothelial lining of pleura. CD26 molecules preferentially expressed on epithelioid type of MPM. This study investigates the molecular mechanisms of CD26 regulating MPM cells in vitro and in vivo. METHODS: Biochemical and cell biological approaches were used for identifying a novel molecular target of MPM. Its contribution to tumour expansion has been also assessed using animal models. The clinical samples of MPM were also assessed for its expression. RESULTS: We identify that cytostatic effects in MPM are mediated by somatostatin (SST) receptor 4 (SSTR4), being inhibited by the interaction of CD26 molecules. We also indicates that SSTR4-mediated cytostatic effects are regulated by SHP-2 PTP, and that this inhibitory effect by SST agonist is enhanced via lipid raft clustering of associated molecules following crosslinking of anti-CD26 antibody. Finally, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment, and that SSTR4 is highly coexpressed with CD26 on epithelioid or biphasic types of MPM tissues obtained from patients' surgical specimens. CONCLUSIONS: Combination therapy with humanised anti-CD26 mAb and SSTR4 agonist may therefore potentiate anti-tumour effect on MPM.

Histamine H1-receptor antagonists with immunomodulating activities: potential use for modulating T helper type 1 (Th1)/Th2 cytokine imbalance and inflammatory responses in allergic diseases.

Being a first-line treatment for hypersensitivity allergic disease, histamine H1-receptor antagonists possess anti-inflammatory activity in addition to being H1-receptor antagonists. While it is not purely a histamine-related condition, hypersensitivity allergic disease is associated with an increase in the number of T helper type 2 (Th2) cells and Th2 cytokines, and a decrease in the number of Th1 cells and Th1 cytokines. Suppression of Th2-type cytokine production in addition to H1-receptor blockade may therefore represent a successful therapeutic strategy for the treatment of hypersensitivity allergic diseases. H1-receptor antagonists have been reported to modulate immune cascade at various points by acting on T cell-related inflammatory molecules, including adhesion molecules, chemokines and inflammatory cytokines. These effects of H1-receptor antagonists may be optimized for the treatment of allergic diseases. Besides their ability to regulate inflammatory molecules, some H1-receptor antagonists have been reported to down-regulate Th2 cytokine production. In particular, it has been shown that several H1-receptor antagonists specifically inhibit the production of Th2, but not Th1, cytokines. Accumulating evidence indicates a crucial role for Th1/Th2 cytokine imbalance on the development of allergic diseases. Accordingly, the use of H1-receptor antagonist with Th2 cytokine inhibitory activity to modulate Th1/Th2 cytokine imbalance might be a favourable strategy for the treatment of hypersensitivity allergic diseases. Furthermore, the identification of H1-receptor antagonists which possess immunoregulatory activities in addition to their anti-histamine activity will provide an important insight into the development of novel immunoregulatory drugs.

CD26 expression on T cell lines increases SDF-1-alpha-mediated invasion.

BACKGROUND: CD26 is a multifunctional membrane-bound glycoprotein that regulates tumour growth in addition to its other activities. Because disease aggressiveness is correlated with CD26 expression in several T-cell malignancies, we decided to investigate the invasiveness of cells expressing different levels of CD26. METHODS: To assess CD26 involvement in cell invasion, we performed in vitro invasion assays with human T cell lines expressing different levels of CD26. These included the parental CD26-positive T-lymphoblast cell line HSB-2 and clones infected with a retrovirus expressing siRNA vectors that either targeted CD26 or encoded a missense siRNA, and the parental CD26-negative T-leukaemia cell line Jurkat and clones expressing CD26. CD26 expression in these cell lines was evaluated by flow cytometry and western immunoblotting. CXCR4 expression, phosphorylation of signalling kinases, and MMP-9 secretion were also evaluated by western immunoblotting, whereas MMP-9 activity and the effect of kinase and CD45 inhibitors on activity were measured by zymography of conditioned media. RESULTS: The presence of CD26 enhanced stromal-cell-derived factor-1-alpha (SDF-1-alpha)-mediated invasion of T cell lines. This process was regulated in part by the PI-3K and MEK1 pathways, as indicated by increased phosphorylation of p44/42 MAP kinase and Akt in the presence of SDF-1-alpha and the effect of their respective inhibitors on MMP-9 secretion and in vitro invasion. In addition, CD26-associated enhancement of SDF-1-alpha-induced invasion was decreased when CD45 was inhibited. CONCLUSIONS: Our results indicate that the expression of CD26 in T cell lines leads to increased SDF-1-alpha-mediated invasion in an in vitro system and that this is controlled in part by the PI-3K and MEK1 pathways. The data also suggest that CD26 enhancement of invasion may be mediated by CD45, however, more studies are required to confirm this involvement.

Crk-associated substrate lymphocyte type regulates transforming growth factor-beta signaling by inhibiting Smad6 and Smad7.

Crk-associated substrate lymphocyte type (Cas-L) is a 105 kDa docking protein with diverse functional properties, including regulation of cell division, proliferation, migration and adhesion. Cas-L is also involved in beta1 integrin- or antigen receptor-mediated signaling in B and T cells. In the present study, we demonstrate that Cas-L potentiates transforming growth factor-beta (TGF-beta) signaling pathway by interacting with Smad6 and Smad7. Immunoprecipitation experiments reveal that single domain deletion of full-length Cas-L completely abolishes its docking function with Smad6 and Smad7, suggesting that the natural structure of Cas-L is necessary for its association with Smad6 and Smad7. On the other hand, both N-terminal and C-terminal deletion mutants of Smad6 and Smad7 still retain their docking ability to Cas-L, suggesting that Smad6 and Smad7 possess several binding motifs to Cas-L. Moreover, Cas-L interaction with Mad-homology (MH)2 domain, but not with MH1 domain of Smad6 or Smad7, ameliorates TGF-beta-induced signaling pathway. Finally, depletion of Cas-L by small-interfering RNA oligo attenuates TGF-beta-induced growth inhibition of Huh-7 cells, with a concomitant reduction in phosphorylation of Smad2 and Smad3. These results strongly suggest that Cas-L is a potential regulator of TGF-beta signaling pathway.

Recurrence of ovarian endometrioma after laparoscopic excision.

BACKGROUND: To analyse risk factors that influence the recurrence of endometrioma after laparoscopic excision. METHODS: A total of 224 patients who had a minimum of 2 years of post-operative follow-up after laparoscopic ovarian endometrioma excision were studied retrospectively. Recurrence was defined as the presence of endometrioma more than 2 cm in size, detected by ultrasonography within 2 years of surgery. Fourteen variables (age, presence of infertility, pain, uterine myoma, adenomyosis, previous medical treatment of endometriosis, previous surgery for ovarian endometriosis, single or multiple cysts, the size of the largest cyst at laparoscopy, unilateral or bilateral involvement, co-existence of deep endometriosis, revised American Society for Reproductive Medicine (ASRM) score, post-operative medical treatment and post-operative pregnancy) were evaluated to assess their independent effects on the recurrence using logistic regression analysis. RESULTS: The overall rate of recurrence was 30.4% (68/224). Significant factors that were independently associated with higher recurrence were previous medical treatment of endometriosis [odds ratio (OR) = 2.324, 95% confidence interval (95% CI) = 1.232-4.383, P = 0.0092) and larger diameter of the largest cyst (OR = 1.182, 95% CI = 1.004-1.391, P = 0.0442). Post-operative pregnancy was associated with lower recurrence (OR = 0.292, 95% CI = 0.028-0.317, P = 0.0181). CONCLUSIONS: Previous medical treatment of endometriosis or large cyst size was a significant factor that was associated with higher recurrence of the disease. Post-operative pregnancy is a favourable prognostic factor.

The tetraspanin CD9 is preferentially expressed on the human CD4(+)CD45RA+ naive T cell population and is involved in T cell activation.

Human CD4+ T cells can be divided into reciprocal memory and naive T cell subsets based on their expression of CD45 isoforms and CD29/integrin beta1 subunit. To identify unique cell surface molecules on human T cells, we developed a new monoclonal antibody termed anti5H9. Binding of anti5H9 triggers a co-stimulatory response in human peripheral blood T cells. Retrovirus-mediated expression cloning has revealed that the antigen recognized by anti5H9 is identical to the tetraspanin CD9. We now show that human CD9 is preferentially expressed on the CD4(+)CD45RA+ naive T cell subset, and that CD9(+)CD45RA+ T cells respond preferentially to the recombinant beta2-glycoprotein I, compared to CD9-CD45RA+ T cells. Furthermore, anti5H9 inhibits both the recombinant beta2-glycoprotein I- and the recall antigen tetanus toxoid-specific T cell proliferation. These results suggest that the tetraspanin CD9 plays an important role in T cell activation.

Rapid inhibitory effect of tacrolimus on T cell migration by suppressing CD29-related functions.

OBJECTIVE: To clarify the direct effect of Tacrolimus (FK506) on T cell function in relation to CD29. METHODS: Human T cell line H9 and phytohemagglutinin (PHA)-activated T cells were incubated with or without Tacrolimus. The cells underwent cell migration assay by using fibronectin-coated trans-wells, and at the same time the degree of adherence by cultured cells to fibronectin-coated plastic wells was measured. For H9 cells, intracellular filamentous actin formation and the cell surface expression of CD3, CD11a, CD25, CD26, CD44, CD29 were measured by using flow cytometry. Intracellular tyrosin-phosphorylation induced by fibronectin by CD29 stimulation in H9 cells was analyzed by immunoblotting. RESULTS: The ability of H9 cells and PHA-activated T cells incubated with Tacrolimus for 2 hours (hrs) to migrate and to adhere to fibronectin was significantly suppressed. However, the inhibiton was transient, because the ability of cells incubated with Tacrolimus for 24 hrs to migrate was not affected despite the suppression of cell replication. Tacrolimus showed slight but significant reduction of cell surface expression of CD29 within 4 hrs, but CD3, CD11a, CD25, CD26 and CD44 were not affected. Tacrolimus rapidly inhibited intracellular filamentous actin formation; the maximum inhibition was within 2 hrs and the effect was not observed at 6 hrs. Intracellular tyrosin-phosphorylation induced by CD29 stimulation was also inhibited by, Tacrolimus in H9 cells. CONCLUSION: Tacrolimus appeared to have transient early phase inhibitory effects on CD29-related function that may be associated with T cell migration.

Ebastine inhibits T cell migration, production of Th2-type cytokines and proinflammatory cytokines.

BACKGROUND: Cytokine imbalance and cellular migration to inflammatory sites are critical components of allergic diseases. Redirecting cytokine imbalance and inhibiting cell migration therefore represent important therapeutic strategies for the treatment of these disorders. OBJECTIVES: To study the in vitro effect of ebastine, a novel non-sedating H1 receptor antagonist, on cytokine secretion and migration of activated T cells, as well as production of pro-inflammatory cytokines by macrophages. METHODS: Peripheral T cells obtained from healthy volunteers were cultured in wells coated with the combination of anti-CD3 monoclonal antibody (mAb) and anti-CD26 mAb, anti-CD3 mAb and anti-CD28 mAb, or anti-CD3 mAb with PMA, in the presence or absence of ebastine. T cell proliferation and the production of cytokines were measured by [3H]thymidine incorporation assay and ELISA, respectively. In addition, transendothelial migration of T cells and production of pro-inflammatory cytokines by macrophages were examined. RESULTS: Ebastine inhibited T cell proliferation and the production of IL-4, IL-5, IL-6, and TNF-alpha by T cells under each co-stimulatory condition tested, whereas it exhibited no effect on the production of IL-2 or IFN-gamma. In addition, T cell migration and the production of such pro-inflammatory cytokines as TNF-alpha and IL-6 by macrophages were inhibited by ebastine. CONCLUSIONS: These results indicate that ebastine has a specific inhibitory effect on Th2-type cytokine production. Moreover, ebastine inhibited T cell migration and pro-inflammatory cytokine production by T cells and macrophages, suggesting that ebastine might be useful for the treatment of T cell-mediated allergic inflammatory disorders, including asthma, atopic dermatitis, and Th2-type autoimmune diseases.

CD26/dipeptidyl peptidase IV enhances expression of topoisomerase II alpha and sensitivity to apoptosis induced by topoisomerase II inhibitors.

CD26/dipeptidyl peptidase IV (DPPIV) is a cell surface-bound ectopeptidase with important roles in T-cell activation and tumour biology. We now report that CD26/DPPIV enhances sensitivity to apoptosis induced by the antineoplastic agents doxorubicin and etoposide. In particular, CD26/DPPIV presence is associated with increased susceptibility to the mitochondrial pathway of apoptosis, documented by enhanced cleavage of poly (ADP ribose) polymerase (PARP), caspase-3 and caspase-9, Bcl-xl, and Apaf-1, as well as increased expression of death receptor 5 (DR5). We also show that the caspase-9-specific inhibitor z-LEHD-fmk inhibits drug-mediated apoptosis, leading to decreased PARP and caspase-3 cleavage, and reduced DR5 expression. Importantly, through detailed studies that demonstrate the association between topoisomerase II alpha expression and DPPIV activity, our data provide further evidence of the key role played by CD26 in biological processes.

Effect of CD26/dipeptidyl peptidase IV on Jurkat sensitivity to G2/M arrest induced by topoisomerase II inhibitors.

CD26/dipeptidyl peptidase IV (DPPIV) is a surface antigen with multiple functions, including a role in T-cell activation and the development of certain human cancers. We previously demonstrated that CD26/DPPIV enhanced sensitivity of Jurkat cells to doxorubicin. We now show that expression of CD26/DPPIV enhanced sensitivity of CD26 Jurkat transfectants to G(2)-M arrest mediated by the antineoplastic agent etoposide. The increased sensitivity to etoposide-induced G(2)-M arrest was associated with disruption of cell cycle-related events, including hyperphosphorylation of p34(cdc2) kinase, change in cdc25C expression and phosphorylation, and alteration in cyclin B1 expression. CD26/DPPIV-associated enhancement of doxorubicin and etoposide-induced G(2)-M arrest was also observed in serum-free media, suggesting an effect of CD26 on cell-derived processes rather than serum-derived factors. Importantly, our work elucidated a potential mechanism for the enhanced susceptibility of CD26-expressing Jurkat cells to the topoisomerase II inhibitors by demonstrating that CD26/DPPIV surface expression was associated with increased topoisomerase II alpha levels and enhanced enzyme activity. Besides being the first to show a functional association between the multifaceted molecule CD26 and the key cellular protein topoisomerase II alpha, our studies provide additional evidence of a potential role for CD26 in the treatment of selected malignancies.

CD26: an expanding role in immune regulation and cancer.

In this review, we highlight major aspects of the biology of CD26, a dipeptidyl peptidase IV (DPPIV)-containing surface glycoprotein with multiple functions. In particular, we discuss findings demonstrating that CD26/DPPIV has an essential role in immune regulation as a T cell activation molecule and a regulator of chemokine function. We also review recent studies that identify key cellular molecules that physically associate with CD26 and the potential consequences of their interaction, including those with clinically-related implications. Furthermore, we present work suggesting a role for CD26 in the pathogenesis and behavior of selected human cancers, both solid tumors and hematological malignancies. We present recent studies that investigate the potential role of CD26 as a molecular target for novel treatment modalities for T cell lymphoid malignancies and possibly other hematological malignancies, with work involving the use of anti-CD26 monoclonal antibody, CD26-transfected cells as well as soluble CD26 molecules.

The hormonal responses of lipoprotein lipase activity and lipolysis in adipose tissue differ depending on the stage of the estrous cycle in female rats.

OBJECTIVE: This study was designed to elucidate whether there were differences in the hormonal responses of the parameters involving triacylglycerol (TG) deposition and mobilization in adipose tissue among the stages of the estrous cycle in female rats. MEASUREMENTS: Adipose tissue was obtained from the parametrial region in female rats at each stage of the estrous cycle. Lipoprotein lipase (LPL) activity in the extracts of acetone/ether powders of the tissues was measured as a parameter for TG deposition. Norepinephrine-stimulated lipolysis in isolated fat cells was measured as a parameter for TG mobilization. RESULTS: LPL activity changed periodically during the estrous cycle; the activity level was highest at diestrus, began to decrease at proestrus, reached a minimum at estrus, began to increase again at metestrus-1, and increased further at metestrus-2. At diestrus and proestrus, LPL activity was increased with an increase in plasma insulin levels, suggesting that plasma insulin was the predominant up-regulator of LPL. But at estrus, metestrus-1 and metestrus-2, LPL activity remained low even when plasma insulin levels were high, indicating that it was not up-regulated by plasma insulin. Norepinephrine-stimulated lipolysis in fat cells was high at estrus and metestrus-1 and low at diestrus. CONCLUSION: The hormonal responses of LPL activity and lipolysis in adipose tissue differed depending on the stage of the estrous cycle.

Soluble CD26/dipeptidyl peptidase IV induces T cell proliferation through CD86 up-regulation on APCs.

CD26 is a T cell costimulatory molecule with dipeptidyl peptidase IV enzyme activity in its extracellular region. We have previously reported that the addition of soluble CD26 (sCD26) resulted in enhanced proliferation of peripheral blood T lymphocytes induced by the recall Ag, tetanus toxoid (TT). However, the mechanism involved in this immune enhancement has not yet been elucidated. In this paper, we demonstrate that the enhancing effect of sCD26 on TT-induced T cell proliferation occurred in the early stages of immune response. The cells directly affected by exogenously added sCD26 are the CD14-positive monocytes in the peripheral blood. Mannose-6 phosphate interfered with the uptake of sCD26 into monocytes, suggesting that mannose-6 phosphate/insulin-like growth factor II receptor plays a role in the transportation of sCD26 into monocytes. When sCD26 was added after Ag presentation had taken place, enhancement in TT-induced T cell proliferation was not observed. In addition, enhancement of TT-mediated T cell proliferation by sCD26 does not result from trimming of the MHC-bound peptide on the surface of monocytes. Importantly, we also showed that exogenously added sCD26 up-regulated the expression of the costimulatory molecule CD86 on monocytes through its dipeptidyl peptidase IV activity, and that this increased expression of CD86 was observed at both protein and mRNA level. Therefore, our findings suggest that sCD26 enhances T cell immune response to recall Ag via its direct effect on APCs.

CD26-mediated signaling for T cell activation occurs in lipid rafts through its association with CD45RO.

CD26 is a T cell activation antigen that contains dipeptidyl peptidase IV activity and is known to bind adenosine deaminase. The mechanism by which CD26 costimulation potentiates T cell receptor-mediated T cell activation, leading to subsequent exertion of T cell effector function, is still not clearly defined. In this article, we demonstrate that CD26 localizes into lipid rafts, and targeting of CD26 to rafts is necessary for signaling events through CD26. Importantly, aggregation of CD26 by anti-CD26 mAb crosslinking also causes coaggregation of CD45 into rafts. Moreover, we show that CD26 directly binds to the cytoplasmic domain of CD45. Our results therefore indicate a mechanism whereby CD26 engagement promotes aggregation of lipid rafts and facilitates colocalization of CD45 to T cell receptor signaling molecules p56(Lck), ZAP-70, and TCRzeta, thereby enhancing protein tyrosine phosphorylation of various signaling molecules and subsequent interleukin-2 production.

Expression of CD26 and its associated dipeptidyl peptidase IV enzyme activity enhances sensitivity to doxorubicin-induced cell cycle arrest at the G(2)/M checkpoint.

CD26, a M(r) 110,000 surface-bound ectopeptidase with dipeptidyl peptidase IV (DPPIV) activity, has an array of diverse functional properties, with a role in T-cell physiology and the development of certain human cancers. In this study, we report that surface expression of CD26, through its associated DPPIV enzyme activity, enhanced sensitivity of Jurkat T-cell transfectants to G(2)-M arrest induced by the chemotherapeutic drug, doxorubicin. This was associated with disruption of cell cycle-related events, including hyperphosphorylation and inhibition of p34(cdc2) kinase activity, phosphorylation of cdc25C, and alteration in cyclin B1 expression. In addition, we demonstrate that the addition of exogenous soluble DPPIV enhanced sensitivity of lymphoid tumor cell lines to doxorubicin, suggesting a potentially useful clinical role for CD26/DPPIV in the treatment of selected human hematological malignancies.