Immune Suppression In Mice Research Articles

Protective Effects of Lactobacillus Strains Against Oxidative Stress and Immune Suppression in Mice Receiving Aflatoxin-Contaminated Diet.

Mycotoxins like aflatoxins pose a significant threat to the health of both people and animals because of their deadly effects. This study aimed to investigate the potential of Lactobacillus strains in reducing the toxicity caused by aflatoxins in mice receiving a diet contaminated with aflatoxins. The mice were split up into various treatment groups, including a control group, an aflatoxin-treated group, and groups treated with the aflatoxin-contaminated diet along with Lactobacillus strains. Various parameters, including liver enzymes, blood parameters, malondialdehyde (MDA) levels, morphometric analysis of ileum, and gene expression, were analyzed to assess the effectiveness of the Lactobacillus strains in mitigating aflatoxins toxicity. Results showed that mice in the aflatoxin-treated group had increased MDA levels, indicating oxidative stress. Alternatively, the Lactobacillus cocktail treatment group showed a decreasing trend in MDA levels, suggesting a reduction in lipid peroxidation. The morphometric analysis of ileum tissue demonstrated that the Lactobacillus-treated group exhibited improved structural integrity compared to the aflatoxin-treated group. Additionally, gene expression analysis revealed that the Lactobacillus treatment attenuated the downregulation of SOD gene expression and mitigated the upregulation of iNOS gene expression induced by aflatoxins. These findings suggest that Lactobacillus strains have the potential to reduce aflatoxin-induced toxicity by alleviating oxidative stress, preserving intestinal tissue integrity, and modulating gene expression associated with antioxidant defense and inflammation. This study provides evidence for the beneficial effects of Lactobacillus strains in reducing aflatoxin toxicity in mice. The findings obtained may contribute to the development of preventive or therapeutic strategies against mycotoxin-induced toxicity.

Free Radical Scavenging Effect and Immunomodulatory Activity of Total Saponins Extract of Ginseng Fibrous Roots.

Ginseng (Panax ginseng C.A. Mey) is known for its rich saponin compounds and tonic effects. To better utilize the medicinal value of ginseng, this study investigated the extraction process, components, free radical scavenging ability, and immunomodulatory activity of total saponins of ginseng fibrous roots. The response surface methodology was employed to optimize the extraction process of total saponins, and Q-Orbitrap high-resolution liquid chromatography-mass spectrometry (LC-MS) was used to identify the chemical constituents in the total saponins extract of ginseng fibrous roots (GRS). The results showed that the optimal extraction process was achieved with an ethanol concentration of 68%, a material-solvent ratio of 1:25 mL/g, and an extraction time of 20 min, yielding a total saponin content of 6.34% under these conditions. The extract contained four terpenoid compounds and four polyphenolic compounds. GRS exhibited considerable scavenging activity against DPPH and ABTS radicals, with IC50 values of 0.893 and 0.210 mg/mL, respectively. Moreover, GRS restored immune suppression in mice by increasing white blood cell, red blood cell, and neutrophil counts, and improving the lymphocyte. It also promoted immune system recovery, as evidenced by elevated serum levels of IL-2, IFN-γ, TNF-α, and IL-1β in mice. GRS is a natural compound with promising potential for developing antioxidants and immunomodulatory foods.

Abstract 3038: PPARδ promotes gastric adenocarcinoma carcinogenesis by enhancing ZBP1-induced necroptosis and inflammation and fostering gastric tumor immunosuppressive microenvironment

Abstract Overexpression of peroxisome proliferator-activated receptor delta (PPARδ) in villin-positive gastric progenitor cells (VGPCs) has been demonstrated to spontaneously induce gastric adenocarcinoma (GAC) in mice. PPARδ is upregulated in human GAC tissues, and its expression level is positively associated with human GAC grades and stages. However, the potential for targeting this tumorigenic effect of PPARδ, along with the underlying molecular mechanisms, remains elusive. In this study, we investigated the impact of PPARδ genetic deletion/loss of function in VGPCs on Helicobacter felis (H. felis)-induced GAC carcinogenesis by orally exposing the mice carrying wild-type (WT) PPARδ or genetically deleted PPARδ in VGPCs to H. felis infection. We also examined the effect of PPARδ inhibition by its specific antagonist, GSK3787, on PPARδ-induced GAC carcinogenesis in mice. Furthermore, we conducted RNA-seq for transcriptomic profiling analysis and validated the results through quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on the gastric tissues of those mice and the mice with WT PPARδ or PPARδ overexpression in VGPCs at ages 10, 25 and 55 weeks. We found that 1) PPARδ genetic deletion in VGPCs significantly inhibited H. felis-induced gastric chronic inflammation and GAC carcinogenesis; GSK3787 significantly suppressed PPARδ-induced GAC carcinogenesis in mice; 2) PPARδ overexpression in VGPCs significantly enhanced while PPARδ genetic deletion in VGPCs significantly inhibited ZBP1-induced necroptosis and the related inflammatory signaling pathways such as interferon-gamma signaling, IL6-JAK-STAT3 signaling, and IL2-STAT5 signaling evidenced by gene set enrichment analysis of RNA-seq data, which were further validated by qRT-PCR; and 3) PPARδ overexpression in VGPCs markedly increased the expression of CCL20 in gastric epithelial cells of the mice before (age 10 weeks) and after GAC initiation and progression (age 25 weeks-early stage GAC and age 55 weeks-late stage GAC), and gastric infiltrations of CCR6+ myeloid-derived suppressor cells and CCR6+ tumor-associated macrophages, thereby creating a gastric tumor immunosuppressive microenvironment. In contrast, PPARδ genetic deletion in VGPCs or the administration of GSK3787 diet significantly reversed this PPARδ-induced immune suppression in mice. In conclusion, our findings highlight the pivotal role of PPARδ in VGPCs as a key host factor in GAC carcinogenesis, especially in individuals exposed to chronic H. pylori infection that could lead to an upregulation of PPARδ expression. This suggests that targeting PPARδ signaling could be a novel therapeutic approach for GAC prevention and therapy. Citation Format: Yi Liu, Daoyan Wei, Lily Wang, James C. Yao, Imad Shureiqi, Xiangsheng Zuo. PPARδ promotes gastric adenocarcinoma carcinogenesis by enhancing ZBP1-induced necroptosis and inflammation and fostering gastric tumor immunosuppressive microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3038.

G-CSF rescue of FOLFIRINOX-induced neutropenia leads to systemic immune suppression in mice and humans

BackgroundRecombinant granulocyte colony-stimulating factor (G-CSF) is routinely administered for prophylaxis or treatment of chemotherapy-induced neutropenia. Chronic myelopoiesis and granulopoiesis in patients with cancer has been shown to induce immature monocytes...

Alhagi honey polysaccharides attenuate intestinal injury and immune suppression in cyclophosphamide-induced mice.

Cyclophosphamide (CY), extensively used as an anti-cancer agent, could cause diverse side effects, such as immunosuppression and intestinal barrier damage. Alhagi honey polysaccharides (AH), polysaccharides isolated from Alhagi honey, are widely known for their anti-tumor and immunomodulatory activities. Herein, AH are evaluated for their ability to protect mice from CY-induced toxicity. The results demonstrated that treatment with AH could prevent the reduction in spleen and thymus indices as well as body weight, and significantly increase the Peyer's patch count in CY-induced mice and the levels of IL-2, IL-6, and TNF-α in serum, suggesting the role of Alhagi honey polysaccharides in alleviating the immunosuppression induced by CY. Moreover, administration of AH significantly increased the SOD activity and the expression level of β-defensin while decreasing the MDA content and DAO activity in CY-treated mice, which suggested a protective effect of AH on the intestinal barrier. Simultaneously, a CY-induced decrease in the ratio of villi length/crypt depth and the number of intraepithelial lymphocytes and goblet cells was reversed by AH treatment, as were the alterations in the expression of ZO-1, mucin-2, E-cadherin and occludin in the intestine and the concentrations of SCFAs in the colon. Furthermore, AH have the ability to regulate the MAPK pathway in CY-mice models to reduce CY-induced toxicity, evidenced by the increased expression of p-ERK and inhibited production of both p-JNK and p-p38. Overall, these results showed that AH could be used as protective agents to mitigate intestinal injury and immune suppression in mice induced by CY.

The Inhibition of Caspase-1- Does Not Revert Particulate Matter (PM)-Induced Lung Immunesuppression in Mice

Background: Air pollution is becoming a threatening issue for human health. Many epidemiological studies relate air pollution index to adverse effects in terms of disease incidence and/or disease exacerbation. In our previous studies, we found air pollutants can induce the release of pro-inflammatory cytokines from human peripheral blood cells. To better understand, the effects of air pollution in the lung, we took advantage of an animal model.Experimental Approach: Mice were intratracheally and daily exposed to urban collected particulate matter (PM, PM10, and PM1) and to the sub-micrometric carbonaceous component, Soot.Results: We found that PM10, PM1, and Soot promoted lung inflammation associated to higher bronchial responsiveness and lower dilation together with an immunosuppressive lung environment, characterized by tolerogenic dendritic cells (DCs), macrophages and myeloid -derived suppressor cells (MDSCs), the latter two Arginase I positive. In support, higher recruitment of Treg associated to higher levels of IL-10 were detected in the lung of PM10, PM1, and Soot treated mice. This effect was not abolished by the administration of a caspase-1 inhibitor, Ac-Y-VAD, implying that the canonical inflammasome complex was not associated to PMx-induced lung immunosuppression in mice.Conclusion: Our study proves that PM exposure leads to an immunosuppressive lung environment in a caspase-1-independent manner, paving the way to understand the molecular and cellular mechanism/s underlying the establishment of some respiratory disorders according to the exposure to air pollution.

IgG-mediated immune suppression in mice is epitope specific except during high epitope density conditions

Specific IgG antibodies, passively administered together with erythrocytes, suppress antibody responses against the erythrocytes. Although used to prevent alloimmunization in Rhesus (Rh)D-negative women carrying RhD-positive fetuses, the mechanism behind is not understood. In mice, IgG suppresses efficiently in the absence of Fcγ-receptors and complement, suggesting an Fc-independent mechanism. In line with this, suppression is frequently restricted to the epitopes to which IgG binds. However, suppression of responses against epitopes not recognized by IgG has also been observed thus arguing against Fc-independence. Here, we explored the possibility that non-epitope specific suppression can be explained by steric hindrance when the suppressive IgG binds to an epitope present at high density. Mice were transfused with IgG anti-4-hydroxy-3-nitrophenylacetyl (NP) together with NP-conjugated sheep red blood cells (SRBC) with high, intermediate, or low NP-density. Antibody titers and the number of single antibody-forming cells were determined. As a rule, IgG suppressed NP- but not SRBC-specific responses (epitope specific suppression). However, there was one exception: suppression of both IgM anti-SRBC and IgM anti-NP responses occurred when high density SRBC-NP was administered (non-epitope specific suppression). These findings answer a longstanding question in antibody feedback regulation and are compatible with the hypothesis that epitope masking explains IgG-mediated immune suppression.

Anti-stress effect of the Lactobacillus pentosus strain S-PT84 in mice.

We investigated if the orally administered Lactobacillus pentosus strain S-PT84 (S-PT84) might show anti-stress activity and ameliorate stress-induced immune suppression in mice. Stress of mice induced an increase in serum corticosterone and a decrease in splenic natural killer activity and in the number of splenocytes versus control mice. However, these changes were not observed in stressed mice that had been administered S-PT84. Furthermore, interleukin (IL)-12 and IL-10 production, which was downregulated in lipopolysaccharide-activated macrophages from stressed mice, was maintained at control levels in the macrophages of stressed mice that had been fed S-PT84. Interferon-γ production, which was downregulated in concanavalin A-activated splenocytes from stressed mice, tended to be maintained at control levels in stressed mice that had been fed S-PT84, although IL-4 production by these cells was not influenced by S-PT84 administration. Additionally, reduced glutathione (GSH) levels were decreased in serum and peritoneal macrophages from stressed mice versus controls, but these GSH levels were significantly higher in stressed animals that had been administered S-PT84 compared with those that had not. These results suggest that S-PT84 exerts anti-stress activity through immune modulation and/or antioxidative activity.

Abstract 2607: Honokiol, a phytochemical from magnolia plant, prevents UV radiation-induced immune suppression in mice through inhibition of PGE2 and DNA methylation

Abstract The exposure of ultraviolet radiation (UVR) to murine skin suppresses the development of allergic contact hypersensitivity (CHS) response which is considered to be a prototypic T-cell mediated immune response. UVR-induced suppression of immune system has been implicated in skin cancer risk. Honokiol has been shown to have anti-skin carcinogenic activity, and here we have assessed the effect of honokiol on UVR-induced immunosuppression and its possible mechanism of action. Our CHS experiments revealed that exposure of C3H/HeN mouse skin with UVB radiation (150 mJ/cm2) for 4 consecutive days resulted in significant suppression of CHS response (75%, P<0.001) to the skin contact sensitizer, 2,4-dinitrofluorobenzene (DNFB), which was associated with the enhancement in the levels of cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production. Topical treatment of mice with honokiol (0.5 and 1.0 mg/cm2 skin area) in hydrophilic-cream based topical formulation or indomethacin (50 μg/mouse), a COX-2 inhibitor, significantly inhibits UV radiation-induced suppression of CHS response (P<0.01-0.005). The exposure of mice with UVB resulted in DNA hypermethylation, increase in DNA methyltransferase (Dnmt) activity, and elevated levels of Dnmt proteins in mouse skin, while treatment of mice with honokiol before each UVB exposure reduced the levels of DNA methylation as well as Dnmt activity compared with non-honokiol-treated control mice. The COX-2 deficient mice are resistant to UV-induced suppression of CHS response. Treatment of UVB exposed COX-2-deficient mice with PGE2 (50 μg/mouse/day) results in UV-induced suppression of CHS, increase in DNA methylation and Dnmt activity in the skin. Further, treatment of honokiol reversed the effect of PGE2 on UV-induced suppression of CHS response in COX-2-deficient mice. Treatment of C3H/HeN mice with 5-aza-2’-deoxycytidine (5-Aza-dc, 1.0 mg/kg body weight, i.p.), a DNA demethylating agent, after each UVB exposure restored the CHS response which was associated with a reduction in Dnmt activity and global DNA methylation levels compared to the UV-exposed mice which were not treated with 5-Aza-dc. We also compared the effect of honokiol with commercially available anti-cancer drugs, such as imiquimod and 5-fluorouracil, on CHS response in UV-exposed mice. Topical treatment of mice with equi-molar concentrations of honokiol and cancer drugs did not show significant difference in terms of inhibition of UVB induced immune suppression and thus suggests honokiol as a substitute for these drugs. These findings provide evidence that honokiol acts through inhibition of inflammatory mediators and subsequently DNA demethylation in UVR-exposed mouse skin. Citation Format: Santosh K. Katiyar, Tripti Singh, Ram Prasad. Honokiol, a phytochemical from magnolia plant, prevents UV radiation-induced immune suppression in mice through inhibition of PGE2 and DNA methylation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2607.

Proanthocyanidins from grape seeds inhibit UV-radiation-induced immune suppression in mice: detection and analysis of molecular and cellular targets.

Ultraviolet (UV)-radiation-induced immunosuppression has been linked with the risk of skin carcinogenesis. Approximately, 2 million new cases of skin cancers, including melanoma and nonmelanoma, diagnosed each year in the USA and therefore have a tremendous bad impact on public health. Dietary phytochemicals are promising options for the development of effective strategy for the prevention of photodamaging effects of UV radiation including the risk of skin cancer. Grape seed proanthocyanidins (GSPs) are such phytochemicals. Dietary administration of GSPs with AIN76A control diet significantly inhibits UV-induced skin tumor development as well as suppression of immune system. UV-induced suppression of immune system is commonly determined using contact hypersensitivity (CHS) model which is a prototype of T-cell-mediated immune response. We present evidence that inhibition of UV-induced suppression of immune system by GSPs is mediated through: (i) the alterations in immunoregulatory cytokines, interleukin (IL)-10 and IL-12, (ii) DNA repair, (iii) stimulation of effector T cells and (iv) DNA repair-dependent functional activation of dendritic cells in mouse model. These information have important implications for the use of GSPs as a dietary supplement in chemoprevention of UV-induced immunosuppression as well as photocarcinogenesis.

Delayed neutralization of interleukin 6 reduces organ injury, selectively suppresses inflammatory mediator, and partially normalizes immune dysfunction following trauma and hemorrhagic shock.

An excessive and uncontrolled systemic inflammatory response is associated with organ failure, immunodepression, and increased susceptibility to nosocomial infection following trauma. Interleukin 6 (IL-6) plays a particularly prominent role in the host immune response after trauma with hemorrhage. However, as a result of its pleiotropic functions, the effect of IL-6 in trauma and hemorrhage is still controversial. It remains unclear whether suppression of IL-6 after hemorrhagic shock and trauma will attenuate organ injury and immunosuppression. In this study, C57BL/6 mice were treated with anti-mouse IL-6 monoclonal antibody immediately prior to resuscitation in an experimental model combining hemorrhagic shock and lower-extremity injury. Interleukin 6 levels and signaling were transiently suppressed following administrations of anti-IL-6 monoclonal antibody following hemorrhagic shock and lower-extremity injury. This resulted in reduced lung and liver injury, as well as suppression in the levels of key inflammatory mediators including IL-10, keratinocyte-derived chemokine, monocyte chemoattractant protein 1, and macrophage inhibitory protein 1α at both 6 and 24 h. Furthermore, the shift to TH2 cytokine production and suppressed lymphocyte response were partly prevented. These results demonstrate that IL-6 is not only a biomarker but also an important driver of injury-induced inflammation and immune suppression in mice. Rapid measurement of IL-6 levels in the early phase of postinjury care could be used to guide IL-6-based interventions.

Dietary selenium protect against redox-mediated immune suppression induced by methylmercury exposure

The antagonism between selenium (Se) and mercury (Hg) has been widely recognized, however, the protective role of Se against methylmercury (MeHg) induced immunotoxicity and the underlying mechanism is still unclear. In the current study, MeHg exposure (0.01mM via drinking water) significantly inhibited the lymphoproliferation and NK cells functions of the female Balb/c mice, while dietary Se supplementation (as Se-rich yeast) partly or fully recovered the observed immunotoxicity, indicating the protective role of Se against MeHg-induced immune suppression in mice. Besides, MeHg exposure promoted the generation of the reactive oxygen species (ROS), reduced the levels of nonenzymic and enzymic antioxidants in target organs, while dietary Se administration significantly diminished the MeHg-induced oxidative stress and subsequent cellular dysfunctions (lipid peroxidation and protein oxidation). Two possible mechanisms of Se’s protective effects were further revealed. Firstly, the reduction of mercury concentrations (less than 25%, modulated by Se supplementation) in the target organs might contribute, but not fully explain the alleviated immune suppression. Secondly and more importantly, Se could help to maintain/or elevate the activities of several key antioxidants, therefore protect the immune cells against MeHg-induced oxidative damage.

Lenalidomide enhances the protective effect of a therapeutic vaccine and reverses immune suppression in mice bearing established lymphomas

Immunomodulatory drugs (IMiDs) are effective therapeutic agents with direct inhibitory effects on malignant B- and plasma-cells and immunomodulatory effects on the T-cell activation. This dual function of IMiDs makes them appealing candidates for combination with a cancer vaccine. We investigated the immune stimulatory effects of lenalidomide, administrated to mice in doses, which provided comparable pharmacokinetics to human patients, on the potency of a novel fusion DNA lymphoma vaccine. The combination was curative in the majority of mice with 8d pre-established syngeneic A20 lymphomas compared with vaccine or lenalidomide alone and induced immune memory. In vivo depletion experiments established the requirement for effector CD8(+) and CD4(+) T cells in protective immunity. Unexpectedly, lenalidomide alone was also associated with reduced numbers of systemic myeloid-derived suppressor cell (MDSC) and regulatory T cell (Treg) in tumor-bearing but not naïve mice, an effect that was independent of simple tumor burden reduction. These results confirm and extend results from other models describing the effect of lenalidomide on enhancing T-cell immunity, highlight the potency of this effect, and provide a rationale for clinical application. Independently, a novel mechanism of action reversing tumor-induced immune suppression by MDSC is suggested.

Astragalus polysaccharides induced gene expression profiling of intraepithelial lymphocytes in immune-suppressed mice

Astragalus polysaccharides (APS) possess a variety of immunomodulatory activities, but the regulation on mucosal immunity is not fully understood. In this study, immune suppression in mice was induced with cyclophosphamide treatment and APS was used as an intervention and was administrated at dosages of 3 g/kg (APS HD) and 1.5 g/kg (APS LD). Intraepithelial lymphocytes (IELs) were isolated from the intestines. The mRNA expressions from IELs in different groups of mice were detected using gene expression microarray to explore the gene expression profile of IELs, and what are the unique pathways related to low and high dosage of APS. Key words: Astragalus polysaccharides, mucosal immunity, intraepithelial lymphocytes, gene expression.

Up-regulation of tim-3 expression contributes to development of burn-induced T cell immune suppression in mice

T cell immunoglobulin and mucin domain 3 (Tim-3) is well known to negatively regulate T cells responses, but its role in burn-induced T cells immune suppression remains unclear. In the present study, in order to identify the relationship between Tim-3 expression and post-burn T cells immune suppression, C57BL/6 mice were subjected to burn injury or sham injury, and the liver and spleen were harvested at the day 1 after operation. The expression level of Tim-3 on hepatic or splenic T cells and the functional properties of Tim-3(+) T cells were evaluated. It was found burn injury induced dramatically elevated Tim-3 expression on both hepatic and splenic CD4(+) and CD8(+) T cells in contrast with the post-burn depletion of T cells. Furthermore, Tim-3 expression was correlated with the suppressive phenotype of T cells following burn injury, including increased expression of anti-inflammatory cytokine IL-10, decreased expression of pro-inflammatory cytokines IFN-γ and TNF-α, reduced T cell proliferation and elevated co-expression of Tim-3 and PD-1. Moreover, Tim-3(+) T cells subsets were more prone to spontaneous apoptosis than Tim-3(-) T cells subsets. Our findings reinforce the idea that the up-regulated expression of Tim-3 on T cells after burn injury plays an important role in the development and maintenance of burn-induced T cell immune suppression.

Oral tolerance induction by partially hydrolyzed whey protein in mice is associated with enhanced numbers of Foxp3+ regulatory T‐cells in the mesenteric lymph nodes

Hypoallergenic formulas are considered a good option for infants at risk for cow's milk allergy. The aim of this animal study was to investigate whether whey hydrolyzates (WH) have the capacity to induce oral tolerance to whey. Whey, partial or extensive WH was given via gavages to naïve mice prior to oral whey sensitization using cholera toxin as an adjuvant. The acute allergic skin response, mouse mast cell protease-1 (mMCP-1), whey-specific IgE, IgG(1) and effector Th2-cells, Th1-cells, and Foxp3(+) regulatory T-cells were determined in the mesenteric lymph nodes (MLN). MLN cells from tolerized mice were adoptively transferred to naïve recipient mice prior to whey sensitization. In contrast to the extensive WH, pre-treatment of naïve mice with whey or partial WH reduced the acute allergic skin response and mast cell degranulation after whey challenge. However, only treatment with whey prevented the generation of serum-specific IgE/IgG(1) . In partial WH tolerized mice, Foxp3(+) regulatory T-cell numbers in the MLN were increased compared to whey-sensitized mice. Both whey and partial WH treatment showed a tendency toward a decreased number of effector Th2-cells. Transfer of MLN cells from tolerized mice protected recipient mice from developing an acute allergic skin response. These results show that partial WH with limited sensitizing properties reduced the effector response upon whey challenge. This effect is transferable using MLN cells and was associated with enhanced Foxp3(+) regulatory T-cell numbers in the MLN. Partial WH retained the capacity to induce active immune suppression in mice which may be relevant for allergy prevention.

Protective effect of a marine oligopeptide preparation from Chum Salmon (Oncorhynchus keta) on radiation‐induced immune suppression in mice

A marine oligopeptide preparation (MOP) obtained from Chum Salmon (Oncorhynchus keta) by the method of enzymatic hydrolysis, has been found to enhance the innate and adaptive immunities through stimulation of the secretion of cytokines in mice. The current study aimed to further investigate the protective effect of MOP on radiation-induced immune suppression in mice. Female ICR mice (6-8 weeks old) were randomly divided into three groups, i.e. blank control, irradiation control and MOP (1.350 g kg(-1) body weight) plus irradiation-treated group. MOP significantly increased the survival rate and prolonged the survival times for 30 days after irradiation, and lessened the radiation-induced suppression of T- or B-lymphocyte proliferation, resulting in the recovery of cell-mediated and humoral immune functions. This effect may be produced by augmentation of the relative numbers of radioresistant CD(4) (+) T cells, enhancement of the level of immunostimulatory cytokine, IL-12, reduction of the level of total cellular NF-κB through the induction of IκB in spleen and inhibition of the apoptosis of splenocytes. We propose that MOP be used as an ideal adjuvant therapy to alleviate radiation-induced injuries in cancer patients.

Photoprotective effects of nicotinamide

Sun protective measures can reduce numbers of both precancerous actinic keratoses and cutaneous squamous cell carcinomas within relatively short periods of time even in high-risk populations. Sunscreens, which tend to provide greater protection against shortwave UVB than against longer wavelength UVA radiation, can however provide only partial protection from the mutagenic and immune suppressive effects of sunlight. In large part, this reflects poor compliance with proper sunscreen application and reapplication. Skin cancer is by far the most common malignancy in Caucasian populations, and additional strategies to reduce the morbidity and economic burden of this disease are now urgently needed. Nicotinamide, the amide form of vitamin B3, is an inexpensive agent which is used for a variety of dermatological applications with little or no toxicity even at high doses. Nicotinamide has photoprotective effects against carcinogenesis and immune suppression in mice, and is photoimmunoprotective in humans when used as a lotion or orally. UV irradiation depletes keratinocytes of cellular energy and nicotinamide, which is a precursor of nicotinamide adenine dinucleotide, may act at least in part by providing energy repletion to irradiated cells.

Cis-Urocanic Acid Stimulates Primary Human Keratinocytes Independently of Serotonin or Platelet-Activating Factor Receptors

Urocanic acid (UCA) is a major epidermal chromophore that undergoes trans to cis isomerization after ultraviolet radiation (UVR). cis-UCA suppresses cell-mediated immunity. Recent studies suggest that cis-UCA binds to serotonin (5-hydroxytryptamine) 2A (5-HT(2A)) receptor and that antagonists of 5-HT(2A) and the platelet-activating factor (PAF) receptor can block cis-UCA-induced immune suppression in mice. Here, we examined the involvement of 5-HT(2A) and PAF receptors in the ability of cis-UCA to stimulate immunomodulatory mediator production in primary human keratinocytes. Using real-time reverse transcription-PCR (RT-PCR), PAF but not 5-HT(2A) receptor mRNA was constitutively expressed in primary human keratinocytes. Treatment with cis-UCA increased prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha), and IL-6 secretion, whereas 5-HT only stimulated IL-6 production. Pretreatment with a 5-HT receptor antagonist partially inhibited IL-6 increase by 5-HT, but did not inhibit mediator production by cis-UCA. Similarly, a PAF receptor antagonist did not inhibit cis-UCA-induced increase in PGE(2). Intracellular calcium mobilization studies using a human epithelial cell line stably transfected with PAF receptor also showed little evidence that cis-UCA stimulated PAF receptor and it did not bind to this receptor. Thus, cis-UCA stimulates mediator production by a pathway that is independent of these receptors in human keratinocytes, and these cells may not be the major target for cis-UCA-induced immune suppression.

Malaria parasite induces tryptophan-related immune suppression in mice

Plasmodium spp. cause the worst parasitic diseases in humans and evade host immunity in complicated ways. Activated catabolism of tryptophan in dendritic cells is thought to suppress immunity, which is mediated by an inducible rate-limiting enzyme of tryptophan catabolism, indoleamine 2,3 dioxygenase (IDO), via both tryptophan depletion and production of toxic metabolites. In various infections, including malaria, IDO is known to be activated but its biological significance is unclear; therefore, we investigated whether malaria parasites induce IDO to suppress host immune responses. We found that enzymatic activity of IDO was elevated systematically in our mouse malaria model, and was abolished by in vivo IDO inhibition with 1-methyl tryptophan. Experimental infection with Plasmodium yoelii showed that IDO inhibition slightly suppressed parasite density in association with enhanced proliferation and IFN-gamma production by CD4+ T cells in response to malaria parasites. Our observations suggest that induction of IDO is one of the immune mechanisms of malaria parasites.