Augmentation of cellular immune response by Ipomoea obscura and Ipobscurine alkaloid attenuates tumor growth in mice

The immune status of the host plays a crucial role in controling the process of carcinogenesis. General or selective activation of various immunocompetent cells and their secretory function to maintain a healthy immune status may help in cancer prophylaxis, as well as therapy. The present study focused on the effect of Ipomoea obscura and Ipobscurine on cell-mediated immune response. In this study we evaluated the effect of I.?obscura and an indole alkaloid fraction from I. obscura on effector mechanisms of cell-mediated immune response by analyzing cytotoxic T lymphocyte (CTL) activity, natural killer (NK) cell activity, antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent complement-mediated cytotoxicity (ACC). The effect of I. obscura and Ipobscurine on interleukin-2 (IL-2) and interferon-γ (IFN-γ) levels was also analyzed. In the in vitro and in vivo systems, I. obscura and Ipobscurine treatment augmented cell-mediated immune response by enhancing the killing activity of CTL and NK cells from splenocytes in normal as well as tumor-bearing mice. ADCC and ACC were also enhanced significantly in both normal and tumor-bearing animals after drug administration, compared with untreated control. Administration of I. obscura and Ipobscurine significantly enhanced the production of IL-2 and IFN-γ in normal as well as tumor-bearing animals. This study reveals that both I. obscura and Ipobscurine have the potential to augment immune response through the enhanced secretion of IL-2 and IFN-γ by T cells and thereby inhibit tumor growth and as an alternative medicine for cancer treatment.     

Safely modulating the immune system in regenerative medicine

The destruction of pluripotent stem cell-derived grafts by the host immune system presents a significant barrier to clinical translation of cell therapies. Pearl et al. (2011) report in this issue of Cell Stem Cell that a brief, nontoxic immunosuppressive regimen, achieved by blockade of leucocyte costimulatory pathways, may overcome this problem.     

Ipobscurines C and D: macrolactam-type indole alkaloids from the seeds of Ipomoea obscura

Separation of the methanolic seed extract of Ipomoea obscura afforded five indole alkaloids, three of them (ipobscurines B-D) being new natural products of a unique structural type characterized as serotonin hydroxycinnamic acid amide-type conjugates with a second phenylpropanoid moiety forming an ether with the 5-OH position of the indole nucleus. Due to an oxidative phenolic coupling between the two phenylpropanoid moieties of the supposed precursor ipobscurine B two 21-membered macrolactams with a phenol ether partial structure are formed: the trans-cis isomers ipobscurines C and D. Their structures were established on the basis of spectral data. Moreover, total synthesis of the racemic erythro- and threo-ipobscurine B 4',4"-dimethyl ethers and the comparison with the corresponding derivative of natural (-)-ipobscurine B proved an erythro configuration of the latter.     

Methyl jasmonate ameliorates lead toxicity in Oryza sativa by modulating chlorophyll metabolism,antioxidative capacity and metal translocation

Lead (Pb) not only negatively alters plant growth and yield but may also have potentially toxic risks to human health. Nevertheless, the interaction between rice (Oryza sativa L.) plants and the molecular cell dynamics induced by lead-methyl jasmonate (MJ) remains unknown. Here, plants were hydroponically exposed to Pb (150 and 300 µM) alone or in combination with 0.5 and 1 µM MJ. The application of MJ modulated the expression of the HMAs, PCS1, PCS2 and ABCC1 genes, thereby immobilizing the Pb in the roots and lessening its translocation to the aerial parts of the rice plant. The supplementation of MJ improved the growth and yield of Pb-stressed rice by adjusting the proline and chlorophyll metabolism, increasing the phytochelatins (PCs) accumulation and diminishing the accumulation of Pb in the shoots. the application of MJ alleviated the oxidative stress of rice plants exposed to Pb toxicity by enhancing the activity of antioxidant enzymes and enzymes of the glyoxalase system (glyoxalase I and II) and decreasing the endogenous levels of malondialdehyde (MDA), hydrogen peroxide (H₂O₂) and methylglyoxal (MG). Therefore, the results of the present study could provide a molecular insight and cellular interplay scheme for the development of a promising strategy in Pb-contaminated areas to produce healthy food.     

Triggering the immune response by proinflammatory cytokines

What determines whether or not an immune response takes place? The older view that it is only the presence or absence of T cells bearing appropriate receptors that matters has been replaced by one which lays at least equal emphasis on inflammation: whether or not antigenpresenting cells become activated and secrete proinflammatory cytokines. The evidence for this view comes partly from older work on animal models of autoimmunity and tolerance, partly signs of “immunological neglect” in transgenic mice akin to “immunological privilege”, and partly from some remarkably supportive genetics. The genetics includes genome scanning for quantitative trait loci determining disease susceptibility and case/control disease associations. Migration inhibitory factor is an interesting proinflammatory cytokine which does not yet fit into this scheme. We ask but do not answer the question whether protective T cell populations are subject to the same rules of activation.     

Arjunarishta alleviates experimental colitis via suppressing proinflammatory cytokine expression,modulating gut microbiota and enhancing antioxidant effect

Molecular Biology Reports - Traditional ayurvedic medicine, Arjunarishta (AA) is used to treat several inflammatory conditions including dysentery associated with blood. The formulation is a...     

Abelmoschus Manihot ameliorates the levels of circulating metabolites in diabetic nephropathy by modulating gut microbiota in non-obese diabetes mice

Huangkui capsule (HKC), a traditional Chinese medicine, has been used for medication of kidney diseases, including diabetic nephropathy (DN). The current study aimed to evaluate the effects of HKC in the modulation of gut microbiota and the amelioration of metabolite levels by using non-obese diabetes (NOD) mice with DN. The microbiota from three parts of intestines (duodenum, ileum and colon) in NOD mice with and without HKC treatment were analysed using 16S rDNA sequencing techniques. Untargeted metabolomics in plasma of NOD mice were analysed with liquid mass spectrometry. Results showed that HKC administration ameliorated DN in NOD mice and the flora in duodenum were more sensitive to HKC intervention, while the flora in colon had more effects on metabolism. The bacterial genera such as Faecalitalea and Muribaculum significantly increased and negatively correlated with most of the altered metabolites after HKC treatment, while Phyllobacterium, Weissella and Akkermansia showed an opposite trend. The plasma metabolites, mainly including amino acids and fatty acids such as methionine sulfoxide, BCAAs and cis-7-Hexadecenoic acid, exhibited a distinct return to normal after HKC treatment. The current study thereby provides experimental evidence suggesting that HKC may modulate gut microbiota and subsequently ameliorate the metabolite levels in DN.     

Flightless-I regulates proinflammatory caspases by selectively modulating intracellular localization and caspase activity

Caspase-1 and caspase-11 are proinflammatory caspases that regulate cytokine production and leukocyte migration during pathogen infection. In an attempt to identify new intracellular regulators of caspase-11, we found that Flightless-I, a member of the gelsolin superfamily of actin-remodeling proteins, interacts and regulates both caspase-11 and caspase-1. Flightless-I targets caspase-11 to the Triton X-100-insoluble cytoskeleton fraction and the cell leading edge. In addition, Flightless-I inhibits caspase-1 activation and caspase-1-mediated interleukine-1beta (IL-1beta) maturation. The physiological relevance of these findings is supported by the opposing effects of Flightless-I overexpression and knockdown on caspase-1 activity and IL-1beta maturation. Our results suggest that Flightless-I may be a bona fide caspase-1 inhibitor that acts through a mechanism similar to that of cytokine response modifier A, a potent caspase-1 inhibitor from the cowpox virus. Our study provides a new mechanism controlling the localization and activation of proinflammatory caspases.     

Modulation of endoperoxide product levels and cyclophosphamide-induced injury by glutathione repletion

Glutathione is a tripeptide important in a number of diverse cellular functions including enzymatic reactions involved in prostaglandin endoperoxide metabolism. We have previously reported that cyclophosphamide administration to rats results in acute lung injury manifested by increased bronchoalveolar lavage albumin concentrations. In the current study we examine whether cyclophosphamide treatment affects pulmonary glutathione stores or bronchoalveolar endoperoxide metabolic product levels and whether these effects may be related to acute lung injury caused by the drug. We show that cyclophosphamide treatment causes a dose-dependent reduction in pulmonary glutathione stores 4 h after drug administration. In addition, acute lung injury as the result of cyclophosphamide can be abrogated by coadministration of oxothiazolidine carboxylate, an intracellular cysteine delivery system that also reverses pulmonary glutathione depletion induced by cyclophosphamide in our study. Finally, cyclophosphamide treatment reduces prostaglandin E2 concentrations in bronchoalveolar lavage and alveolar macrophage culture supernatant in a dose-dependent fashion and increases bronchoalveolar thromboxane concentrations in low dose-treated animals. These effects are reversed to a variable degree by coadministration of oxothiazolidine carboxylate. Our study suggests in vivo pulmonary arachidonic acid metabolism and cyclophosphamide-induced acute lung injury are modulated by cellular glutathione stores. These findings may have important implications for the treatment of acute lung injury.     

Targeting unique tumor antigens and modulating the cytokine environment may improve immunotherapy for tumors with immune escape mechanisms

Cytotoxic T-cell responses to shared tumor antigens have been characterized for several tumor types, and the MHC-associated peptides that comprise these antigens have been defined at a molecular level. These provide new tools to determine whether immune responses can be generated with these tumor antigens, and there are data to suggest that such immune responses can be generated. However, it is also clear that tumor cells can evade immune responses directed against some shared antigens, by downregulating expression of MHC or of the antigenic protein(s), as well as by more active methods such as secretion of immunosuppressive cytokines. Awareness of these mechanisms of immune escape will help to direct development of the next generation of tumor vaccines. Targeting unique antigens and modulating the cytokine environment likely will be critical to comprehensive vaccine systems in the future. Received: 20 March 1999 / Accepted: 3 May 1999     

Activation and suppression of the proinflammatory immune response by Vibrio cholerae toxins

Vibrio cholerae induces either non-inflammatory diarrhea or inflammatory gastroenteritis, depending on the presence of cholera toxin, a fluid secretion inducer and a modulator of host immunity. In the absence of cholera toxin, other toxins induce inflammation, resulting in gastroenteritis. Thus, multiple toxins likely affect the safety of live attenuated vaccines.     

Androstenediol ameliorates alterations in immune cells cytokine production capacity in a two-hit model of trauma-hemorrhage and sepsis

Although administration of androstenediol (a metabolite of dehydroepiandrosterone) following trauma-hemorrhage (T-H) produces beneficial effects on inflammatory cytokines and organ function, it remains unknown whether this metabolite has any salutary effects in preventing alterations in immune cell cytokine production following a combined insult of T-H and sepsis. To examine this, male rats underwent laparotomy, hemorrhagic shock (mean BP 40 mmHg for 90 min) and resuscitation or sham operation. Androstenediol (1 mg/kg BW i.v.) or vehicle was administered at the end of resuscitation. Twenty hrs after T-H or sham operation, sepsis was induced by cecal ligation and puncture (CLP). Five hours thereafter, plasma cytokine levels and cytokine production of various immune cells were determined. In a separate set of experiments, survival was monitored for 10 days after the induction of sepsis. Administration of androstenediol markedly decreased plasma IL-6 and TNF-alpha levels following T-H and CLP. Furthermore, it prevented the increased production of IL-6 and TNF-alpha by Kupffer cells and alveolar macrophages and attenuated the decrease in IL-6 and TNF-alpha production by splenic macrophages; however, it had no significant effects on the depressed IL-6 and TNF-alpha production by PBMC following T-H and CLP. The depressed IL-2 and IFN-gamma production by splenocytes under those conditions was attenuated by the administration of androstenediol. Furthermore, survival rate following T-H and subsequent sepsis was improved by androstenediol treatment. Since androstenediol administration following T-H attenuated cytokine production and reduced mortality in a double-hit model of T-H and sepsis, this agent appears to be a novel and useful adjunct for maintaining the immune cell functions following T-H and for decreasing the mortality rate from subsequent susceptibility to sepsis.     

Hyperbaric oxygen therapy ameliorates osteonecrosis in patients by modulating inflammation and oxidative stress

Early stages of avascular necrosis of the femoral head (AVNFH) can be conservatively treated with hyperbaric oxygen therapy (HBOT). This study investigated how HBOT modulates inflammatory markers and reactive oxygen species (ROS) in patients with AVNFH. Twenty-three male patients were treated with two cycles of HBOT, 30 sessions each with a 30 days break between cycles. Each session consisted of 90?minutes of 100% inspired oxygen at 2.5 absolute atmospheres of pressure. Plasma levels of tumor necrosis factor alfa (TNF-α), interleukin 6 (IL-6), interleukin 1 beta (IL-1β) and ROS production were measured before treatment (T0), after 15 and 30 HBOT sessions (T1 and T2), after the 30-day break (T3), and after 60 sessions (T4). Results showed a significant reduction in TNF-α and IL-6 plasma levels over time. This decrease in inflammatory markers mirrored observed reductions in bone marrow edema and reductions in patient self-reported pain.     

Suppression of proinflammatory cytokine expression by herpes simplex virus type 1

Viral immune evasion strategies are important for establishment and maintenance of infections. Many viruses are in possession of mechanisms to counteract the antiviral response raised by the infected host. Here we show that a herpes simplex virus type 1 (HSV-1) mutant lacking functional viral protein 16 (VP16)-a tegument protein promoting viral gene expression-induced significantly higher levels of proinflammatory cytokines than wild-type HSV-1. This was observed in several cell lines and primary murine macrophages, as well as in peritoneal cells harvested from mice infected in vivo. The enhanced ability to stimulate cytokine expression in the absence of VP16 was not mediated directly by VP16 but was dependent on the viral immediate-early genes for infected cell protein 4 (ICP4) and ICP27, which are expressed in a VP16-dependent manner during primary HSV infection. The virus appeared to target cellular factors other than interferon-induced double-stranded RNA-activated protein kinase R (PKR), since the virus mutants remained stronger inducers of cytokines in cells stably expressing a dominant-negative mutant form of PKR. Finally, mRNA stability assay revealed a significantly longer half-life for interleukin-6 mRNA after infection with the VP16 mutant than after infection with the wild-type virus. Thus, HSV is able to suppress expression of proinflammatory cytokines by decreasing the stability of mRNAs, thereby potentially impeding the antiviral host response to infection.     

Longitudinal modulation of immune system cytokine profile during pregnancy

ObjectiveTo characterize immune modulation as expressed by cytokine assays at three time-points in human pregnancy.Study designThis is a prospective, longitudinal study of a broad panel of cytokine expression during singleton pregnancies resulting in an uncomplicated, full-term, live births. Peripheral blood was obtained at 8–14, 18–22, and 28–32 weeks gestation. Six cytokines – IFN-γ, IL-4, TNF-α, IL-1β, IL-6, and IL-10 – were measured in supernatants obtained from whole blood stimulations with PHA or LPS and were compared to unstimulated controls. Samples were processed by Luminex-100 MAP®. We used Generalized Linear Models (GLM) to evaluate cytokine trajectories.ResultsComplete data were obtained for 45 uncomplicated pregnancies. Overall, peripheral blood WBC’s demonstrated dampened cytokine responses. However, over the course of pregnancy, we found enhanced counter-regulatory cytokine expression (e.g., shown by increased IL-10).ConclusionThe overall decrease in pro-inflammatory cytokines and increase in counter-regulatory cytokines as uncomplicated pregnancy progresses supports the evolving concepts of immunoregulation for the maintenance of a viable pregnancy.     

Suppressors of cytokine signalling (SOCS) in the immune system

The suppressors of cytokine signalling (SOCS) are a family of intracellular proteins, several of which have emerged as key physiological regulators of cytokine responses, including those that regulate the immune system. The SOCS proteins seem to regulate signal transduction by combining direct inhibitory interactions with cytokine receptors and signalling proteins with a generic mechanism of targeting associated proteins for degradation. Evidence is emerging for the involvement of SOCS proteins in diseases of the human immune system, which raises the possibility that therapeutic strategies that are based on the manipulation of SOCS activity might be of clinical benefit.     

Tumor-associated antigens are cytokine inducers and hyporeactivity factors to the immune system

We investigated possible mechanisms leading to the inhibition of theimmune system in people with chronic disorders. Tumor cell produce proteinreleased into the circulation, such as tumor associated antigens, may playan important role in processes preceding paralysis of the immune system. Totest this hypothesis the following tumor associated antigens were used: AFP,OFP, CA-125, CA-50 and CA-19-9. Their role was assessed by modulatingcytokine production in cord blood lymphocytes and peripheral white bloodcells obtained from grown population of patients treated with colostrinin,an cytokine inducer. PHA, LPS and colostrinin were used as positive controlin those essays. Each antigen tested individually induced IFN, TNFand IL-6 in dose dependent fashion. None of the tested cytokines werespontaneously released by the cells. Data generated from these experimentsindicated that tumor associated antigens are inducing type 1 cytokines insimilar fashion as LPS or colostrinin. However, lymphocytes taken frompatients undergoing therapy with colostrinin revealed progressive losscapability to produce type 1 cytokines as they did in case of colostrinin.The loss of the capability to respond to antigen may represent phenomenonleading to immune tolerance.     

Role of epiregulin in peptidoglycan-induced proinflammatory cytokine production by antigen presenting cells

We have previously found that epiregulin, a member of epidermal growth factor superfamily, is involved in proinflammatory cytokine production in bone marrow-derived macrophages. In this report, to further assess the role of epiregulin in innate immunity, we measured IL-6 production levels upon lipopolysaccharide and peptidoglycan stimulation in antigen presenting cells including macrophages and dendritic cells. Our analyses using epiregulin-deficient mice with mixed and inbred genetic backgrounds revealed that epiregulin deficiency results in the reduction of IL-6 production levels in both cell types upon peptidoglycan stimulation, and that the extent of this reduction is more evident under the BALB/c background compared with the C57BL/6J background. These results indicated that epiregulin may have a critical role in the regulation of peptidoglycan-mediated proinflammatory cytokine production in antigen presenting cells and innate immunity.