Modulation Of Cytokine Responses Research Articles

Adenosine Receptor Antagonists Effect on Plasma-Enhanced Killing

Previous studies demonstrated that naive plasma has inherent capabilities to enhance bacterial opsonization and phagocyte killing, but not all plasma is equally effective. This raised the question of whether plasma constituents other than opsonins may play a role. Adenosine receptor antagonists have been shown to modulate cytokine response and survival in mice after a bacterial challenge. We investigated whether selective adenosine receptor blockade would influence the ability of naive plasma to effectively control bacterial growth. Colonic bacteria- and thioglycollate-elicited peritoneal macrophages and neutrophils were obtained from naive mice. Stock murine plasma from naive was purchased and categorized as having high plasma-enhanced bacterial killing capacity using our previously described methods. Bacteria and plasma were incubated to allow for opsonization and then added to macrophages previously exposed to selected adenosine receptor antagonists: ZM 241385: A2A, MRS1754: A2B, DPCPX: A1, and MRS1220: A3. The final mixture was plated on blood agar plates in aerobic and anaerobic conditions and bacterial colony-forming units quantified after 24 h. This study demonstrated that exogenous adenosine was able to significantly decrease phagocyte killing of cecal bacteria. Blocking adenosine receptors with selective antagonists altered the bacterial killing capacity of plasma. Selectively blocking the A1, A2A, or A2B receptors proved most beneficial at reversing the effect of adenosine. Consistent with previous work, only macrophage killing of bacteria could be modulated by adenosine receptor blockade because neutrophils were unaffected. These data demonstrate that adenosine decreases macrophage killing of enteric bacteria and that this effect is mediated through the adenosine receptors.

Loss of translation: a stealth weapon against pathogens?

Various receptors alert cells to microbial invasion through the detection of conserved molecular patterns and initiate innate immunity. During infection with Legionella pneumophila, macrophages modulate cytokine responses by downregulating protein synthesis according to the pathogenic potential of the intruder.

Inhibition of Toll-Like Receptor 2–Mediated NF-κB Activation in Vero Cells with Herpesvirus of Turkeys

In a previous study, vaccination with a live bivalent vaccine consisting of herpesvirus of turkeys (HVT) and SB-1 was found to be associated with distinct cytokine expression patterns and the modulation of cytokine responses in the spleen. This vaccine could play a role in mediating protection against infection with the RB1B strain of Marek's disease virus. In the present study, vectors for chicken Toll-like receptor 1 (chTLR1) and 2 (chTLR2) expression were constructed and transfected into Vero cells. Nuclear factor kappa light-chain enhancer of activated B cell (NF-kappaB) activation was detected after HVT infection. Compared with normal Vero cells, NF-kappaB activation was significantly inhibited by HVT in Vero cells transfected with chTLR1-1, chTLR1-2, or both. The results demonstrate the significant characteristics of HVT in activating TLR2 signaling. chTLR1 plays a key role in TLR2 subfamily-mediated NF-kappaB inhibition after HVT infection.

Role of NOD1 polymorphism in susceptibility and clinical progression of rheumatoid arthritis

One of the disease hallmarks of RA is progressive cartilage and bone destruction in the joints. The exact mechanism underlying this disease process is largely unknown. Nod1, an intracellular pattern recognition receptor expressed by the innate immune system, has been previously shown to display anti-inflammatory effects in experimental arthritis. Furthermore, an insertion/deletion polymorphism in NOD1 has been demonstrated to modulate cytokine responses of immune cells. In this study, the effect of the insertion/deletion polymorphism in NOD1 on RA susceptibility and severity was assessed. Ex vivo stimulation of primary immune cells and osteoclasts with microbial triggers was performed to measure cytokine responses and osteoclast-specific gene expression in relation to the NOD1 genotype. In total, 1047 RA patients from two centres were genotyped for the NOD1 polymorphism and compared with 431 healthy controls. Clinical scores of joint inflammation and destruction were correlated with the NOD1 genotype. Functional analysis revealed increased production of pro-inflammatory cytokines in cells from individuals bearing the NOD1 +32656 insertion allele. Furthermore, osteoclast bone resorption activity was elevated, as reflected by increased expression of the lysosomal protease cathepsin K. However, the insertion allele of the NOD1 +32656 polymorphism was not associated with either susceptibility to, or clinical parameters of, inflammation or bone destruction in RA patients. These findings demonstrate that the NOD1 polymorphism modulates pro-inflammatory cytokine responses induced through Toll-like receptor or Nod-like receptor ligands. Nevertheless, these effects of genetic variation in NOD1 appear to be redundant in RA susceptibility and severity.

The EBV immunoevasins vIL-10 and BNLF2a protect newly infected B cells from immune recognition and elimination.

Lifelong persistence of Epstein-Barr virus (EBV) in infected hosts is mainly owed to the virus' pronounced abilities to evade immune responses of its human host. Active immune evasion mechanisms reduce the immunogenicity of infected cells and are known to be of major importance during lytic infection. The EBV genes BCRF1 and BNLF2a encode the viral homologue of IL-10 (vIL-10) and an inhibitor of the transporter associated with antigen processing (TAP), respectively. Both are known immunoevasins in EBV's lytic phase. Here we describe that BCRF1 and BNLF2a are functionally expressed instantly upon infection of primary B cells. Using EBV mutants deficient in BCRF1 and BNLF2a, we show that both factors contribute to evading EBV-specific immune responses during the earliest phase of infection. vIL-10 impairs NK cell mediated killing of infected B cells, interferes with CD4+ T-cell activity, and modulates cytokine responses, while BNLF2a reduces antigen presentation and recognition of newly infected cells by EBV-specific CD8+ T cells. Together, both factors significantly diminish the immunogenicity of EBV-infected cells during the initial, pre-latent phase of infection and may improve the establishment of a latent EBV infection in vivo.

Lactobacillus acidophilus and Lactobacillus reuteri modulate cytokine responses in gnotobiotic pigs infected with human rotavirus

Probiotic lactic acid bacteria (LAB) have been shown to alleviate inflammation, enhance the immunogenicity of rotavirus vaccines, or reduce the severity of rotavirus diarrhoea. Although the mechanisms are not clear, the differential Th1/Th2/Th3-driving capacities and modulating effects on cytokine production of different LAB strains may be the key. Our goal was to delineate the influence of combining two probiotic strains of Lactobacillus acidophilus and Lactobacillus reuteri on the development of cytokine responses in neonatal gnotobiotic pigs infected with human rotavirus (HRV). We demonstrated that HRV alone, or HRV plus LAB, but not LAB alone, initiated serum cytokine responses, as indicated by significantly higher concentrations of IFN-α, IFN-γ, IL-12, and IL-10 at postinoculation day (PID) 2 in the HRV only and LAB+HRV+ pigs compared to LAB only and LAB-HRV- pigs. Peak cytokine responses coincided with the peak of HRV replication. LAB further enhanced the Th1 and Th2 cytokine responses to HRV infection as indicated by significantly higher concentrations of IL-12, IFN-γ, IL-4 and IL-10 in the LAB+HRV+ pigs compared to the LAB-HRV+ pigs. The LAB+HRV+ pigs maintained relatively constant concentrations of TGF-β compared to the HRV only group which had a significant increase at PID 2 and decrease at PID 7, suggesting a regulatory role of LAB in maintaining gut homeostasis. At PID 28, cytokine secreting cell (CSC) responses, measured by ELISpot, showed increased Th1 (IL-12, IFN-γ) CSC numbers in the LAB+HRV+ and LAB-HRV+ groups compared to LAB only and LAB-HRV- pigs, with significantly increased IL-12 CSCs in spleen and PBMCs and IFN-γ CSCs in spleen of the LAB+HRV+ group. Thus, HRV infection alone, but not LAB alone was effective in inducing cytokine responses but LAB significantly enhanced both Th1 and Th2 cytokines in HRV-infected pigs. LAB may also help to maintain immunological homeostasis during HRV infection by regulating TGF-β production.

Neonatal revaccination with Bacillus Calmette–Guérin elicits improved, early protection against Mycobacterium tuberculosis in mice

The protective effect of revaccination with Mycobacterium bovis Bacillus Calmette–Guérin (BCG) against Mycobacterium tuberculosis in animals is controversial. To investigate whether revaccination of neonates with BCG could improve the protection against M. tuberculosis, C57BL/6 neonates were vaccinated with BCG on day 1, or on days 1, 7, and 14, and the mice at eight weeks of age were challenged with M. tuberculosis and monitored for survival. The M. tuberculosis burden in their livers and lungs, the pathological changes in the lungs, their splenic T cell responses and serum cytokines were examined longitudinally post-challenge. BCG vaccination significantly prevented the M. tuberculosis-related mouse death and reduced the burden of M. tuberculosis in the liver and lungs, and lung damage in the mice, particularly at early stage of the pathogenic process in the BCG-revaccinated mice. However, the BCG revaccination-induced protection waned over time. BCG vaccination did not significantly modulate the levels of serum IFN-γ and the frequency of splenic PPD-reactive IFN-γ-secreting T cells, but significantly decreased the levels of serum TNF-α and PPD-specific IL-4 responses at 3 weeks post challenge. Taken together, these data suggest that revaccination of neonates with BCG elicits improved, early protection against M. tuberculosis by modulating cytokine responses in adult mice.

To Grow or to Age: New Research in Growth Hormone

GH is a hormone with diverse actions. As the name implies, GH plays a critical role in body growth. At the onset of puberty, GH reaches its peak level, leading to the elongation of the long bones and rapid linear growth. GH induces the expression of insulinlike growth factor-1 (IGF-1) in the liver, which mediates part of the growth-promoting action of GH. GH and IGF-1 both decline rapidly from early teens and decline thereafter as a function of age. Another well-known action of GH is the anabolic effect in the skeletal muscle, resulting in enhanced protein synthesis and increased muscle mass. In contrast, GH induces a catabolic effect in the adipose tissue, resulting in fat loss [3]. Because of these effects in the muscle and fat, GH is often abused and mis-used by athletes. In addition to these classical actions of GH, other documented although less-well studied effects of GH include fluid retention, reproduction and immunity. GH acts on the renin-angiotensin-aldosterone system to promote fluid retention [4]. In this regard, both extracellular volume and plasma volume are decreased in GH deficient patients and normalized after GH replacement therapy [4]. GH also regulates reproduction. Normal GH signaling is needed for folliculogenesis, ovarian maturation, ovulation, and pregnancy in females and for spermatogenesis and the Leydig cell function in males [5]. Adding to its diverse physiological effects, GH also plays an important role in immune modulation. It stimulates T and B cells proliferation and immunoglobulin synthesis, promoting the differentiation of myeloid progenitor cells and modulates cytokine response [6]. These physiological effects of GH warrant further study to understand the related health issues and potential applications in therapeutics. In recent years, GH has been shown to regulate aging. Animal studies have demonstrated that disrupted GH signaling results in increased longevity [7], whereas increased GH signaling leads to premature aging [8,9]. Thus GH shows a pleiotropic effect- beneficial at early age for fitness and reproduction while detrimental at old age [10]. The mechanism for the aging promoting effect is not completely understood, but may involve increased insulin resistance and cancer incidence, and reduced stress defense and mitochondria functions associated with prolonged increase of GH signaling [10]. In humans, acromegaly, a disorder of excess GH secretion, is known to be associated with hypertension, cardiovascular anomaly, diabetes, respiratory problems and increased mortality if untreated [11], which is consistent with studies of GH transgenic mice. However, increased lifespan has not been observed in Laron Syndrome subjects, who have mutations in their GH receptor (GHR) gene therefore no GH signaling. This is in contrast to GHR null mice which show a 50% increase in lifespan compared to control mice. Interestingly though, Laron subjects have a decreased incidence of cancer and diabetes [12], thus supporting the

Salidroside attenuates LPS-induced pro-inflammatory cytokine responses and improves survival in murine endotoxemia

Salidroside is a major component isolated from the Rhodiola rosea. In the present study, we investigated the anti-inflammatory effects of salidroside on cytokine production by lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages in vitro, and the results showed that salidroside reduced tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) secretions. This inspired us to further study the effects of salidroside in vivo. Salidroside significantly attenuated TNF-α, IL-1β and IL-6 productions in serum from mice challenged with LPS, and consistent with the results in vitro. In the murine model of endotoxemia, mice were treated with salidroside prior to or after LPS challenge. The results showed that salidroside significantly increased mouse survival. Further studies revealed that salidroside could downregulate LPS-induced nuclear transcription factor-қB (NF-қB) DNA-binding activation and ERK/MAPKs signal transduction pathways production in RAW 264.7 macrophages. These observations indicated that salidroside modulated early cytokine responses by blocking NF-қB and ERK/MAPKs activation, and thus, increased mouse survival. These effects of salidroside may be of potential usefulness in the treatment of inflammation-mediated endotoxemia.

Role of Cytokines in the Pathogenesis and Suppression of Thyroid Autoimmunity

Autoimmune thyroid diseases (AITD) are one of the most common organ-specific autoimmune disorders, of which Hashimoto's thyroiditis (HT) and Graves' disease (GD) are 2 of the most common clinical expressions. HT is characterized by hypothyroidism that results from the destruction of the thyroid by thyroglobulin-specific T cell-mediated autoimmune response. In contrast, GD is characterized by hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor-specific stimulatory autoantibodies. Cytokines play a crucial role in modulating immune responses that affect the balance between maintenance of self-tolerance and initiation of autoimmunity. However, the role of cytokines is often confusing and is neither independent nor exclusive of other immune mediators. A regulatory cytokine may either favor induction of tolerance against thyroid autoimmune disease or favor activation and/or exacerbation of autoimmune responses. These apparently contradictory functions of a given cytokine are primarily influenced by the nature of co-signaling delivered by other cytokines. Consequently, a thorough understanding of the role of a particular cytokine in the context of a specific immune response is essential for the development of appropriate strategies to modulate cytokine responses to maintain or restore health. This review provides a summary of recent research pertaining to the role of cytokines in the pathogenesis of AITD with a particular emphasis on the therapeutic applications of cytokine modulation.

The different expression of immune-related cytokine genes in response to velogenic and lentogenic Newcastle disease viruses infection in chicken peripheral blood

Newcastle disease virus (NDV) is an important pathogen hazardous to poultry industry, and the pathogenicity of NDV strains varies with different virulence. Peripheral blood serves as an important producer and carrier of viruses and cytokines in NDV infection. In order to explore the difference of cytokine expression in the peripheral blood between velogenic strain and lentogenic strain infection, NDV virulent strain F48E9 and vaccine strain Lasota were used to infect specific-pathogen-free (SPF) chickens separately, and peripheral blood was collected on 0, 3, 7, 10, 14, and 21days post-infection (d.p.i.). Real-time PCR was then used to detect the expression of six kinds of immune-related cytokine genes. For the F48E9 group, a sharp increase of the expression of interferon-alpha (IFN-α), interferon-gamma (IFN-γ), interleukin-16 and IL-18 was observed on 3d.p.i. before the NDV blood peak (7d.p.i.), followed by a rapid decline to the level lower than that of control group, then the expression of IFN-α increased slowly and reached or exceeded the level of control group in the later phase of the infection, while the expression of IFN-γ, IL-16, and IL-18 fluctuated at the level of control group for the rest of study period. The increase of IL-2 expression was not obvious, and no increase of IL-15 expression was noted. For the Lasota (vaccine) group, the picture was quite different, a sharp increase of IFN-γ (but not IFN-α), IL-2 was observed on 7d.p.i. before the NDV blood peak (10d.p.i.). On the contrary, there was no dramatic increase of IL-16 and IL-18. Interestingly, in contrast to the F48E9 group, there was an increase of IL-15 on day 10d.p.i., but it remained modest. There was also an increase of IFN-α on day 21d.p.i. Our results revealed that infection with NDV strains of different virulence was associated with distinct cytokine expression patterns in peripheral blood, modulation of cytokine responses may play a key role in mediation of NDV pathogenesis.

Sequential phosphorylation and ubiquitination regulate NOD2:RIP2 signaling (157.7)

Abstract NOD2, the Crohn’s Disease and sarcoidosis susceptibility protein, is an intracellular sensor of muramyl dipeptide (MDP), a breakdown product of bacterial peptidoglycan. Upon exposure to MDP, NOD2 binds to the kinase RIP2 to modulate cytokine responses. We have recently described that NOD2 activation results in the tyrosine autophosphorylation of RIP2 and have demonstrated that pharmacologic inhibition of RIP2’s tyrosine kinase activity blunts activation of downstream NOD2 signal transduction pathways. In complementarly work, the E3 ubiquitin ligase, ITCH, downregulates NOD2 signaling, and in ITCH-/- macrophages or ITCH knockdown cells, both MDP-induced cytokine release and RIP2 tyrosine phosphorylation are aberrantly high. Our current work extends these findings by demonstrating that ITCH-/- mice are hypersensitive to sarcoidosis models. We molecularly map the direct site of ITCH-induced downregulation of the NOD2:RIP2 pathway and find that ITCH mediates regulation of NOD2 signaling and RIP2 tyrosine phosphorylation through ubiquitination and degradation of cIAP1. Lastly, we show that by mimicking the action of ITCH through the use of pharmacological inhibitors of cIAP1 (MEBS), we can decrease levels of cIAP1, decrease RIP2 tyrosine phosphorylation, and negatively regulate downstream NOD2 signaling. Agents such as MEBS may be useful in hyperactive NOD2 states such as in individuals with Crohn’s Disease harboring WT NOD2, Early Onset Sarcoidosis, and ITCH-deficiency.

Evaluation of immune responses following infection of ponies with an EHV-1 ORF1/2 deletion mutant

Equine herpesvirus-1 (EHV-1) infection remains a significant problem despite the widespread use of vaccines. The inability to generate a protective immune response to EHV-1 vaccination or infection is thought to be due to immunomodulatory properties of the virus, and the ORF1 and ORF2 gene products have been hypothesized as potential candidates with immunoregulatory properties. A pony infection study was performed to define immune responses to EHV-1, and to determine if an EHV-1 ORF1/2 deletion mutant (ΔORF1/2) would have different disease and immunoregulatory effects compared to wild type EHV-1 (WT). Infection with either virus led to cytokine responses that coincided with the course of clinical disease, particularly the biphasic pyrexia, which correlates with respiratory disease and viremia, respectively. Similarly, both viruses caused suppression of proliferative T-cell responses on day 7 post infection (pi). The ΔORF1/ORF2 virus caused significantly shorter primary pyrexia and significantly reduced nasal shedding, and an attenuated decrease in PBMC IL-8 as well as increased Tbet responses compared to WT-infected ponies. In conclusion, our findings are (i) that infection of ponies with EHV-1 leads to modulation of immune responses, which are correlated with disease pathogenesis, and (ii) that the ORF1/2 genes are of importance for disease outcome and modulation of cytokine responses.

Immunological Response to (1,4)‐α‐d‐Glucan in the Lung and Spleen of Endotoxin‐Stimulated Juvenile Rats

We investigated the effects of (1,4)-alpha-D-glucan (alpha-DG), a novel immune stimulatory drug from Tinospora cordifolia, on the concentration of pro- and anti-inflammatory cytokines (interleukin [IL]-1beta, IL-6, tumour necrosis factor-alpha [TNF-alpha], gamma-interferon [IFN-gamma] and IL-10) in the lung and spleen of endotoxin-stimulated juvenile rats. Experimental groups (n = 16/group) included controls with an intraperitoneal injection of saline, endotoxaemic rats with a non-lethal dose of 10 mg/kg Escherichia coli endotoxin, and endotoxaemic rats treated with two doses of 10 mg/kg alpha-DG, intraperitoneally, 2 and 4 hr after endotoxin injection. At 24 hr of treatment, rats were euthanized and lungs and spleen were removed for cytokines determination and lung injury. Endotoxaemia increased IL-1beta concentration by fivefold in both organs, while creating a moderate pulmonary hypercellularity (demonstrated by about 11% increase in the alveolar-septal thickening and 11% decrease in the alveolar-interstitial space ratio). In the lung, alpha-DG treatment reduced concentrations of IL-1beta by 30% (p > 0.05), IL-6 by 43% (p < 0.01), IFN-gamma by 46% (p < 0.01) and the anti-inflammatory cytokine, IL-10, by 31% (p > 0.05) compared to endotoxaemia. In the spleen, alpha-DG treatment decreased the ratio of IL-1beta to IL-10 by 55% (p < 0.05), demonstrating an anti-inflammatory trend. These data suggest that alpha-DG differentially modulates cytokine response in the lung and spleen and modifies the pro- and anti-inflammatory balance during an early period of endotoxaemia in juvenile rats.

PRRSv modulate cytokine response of porcine dendritic cells and compromise the activation of T cells

PRRSv modulate cytokine response of porcine dendritic cells and compromise the activation of T cells

Effect of HLA Genotype or CTLA‐4 Polymorphism on Cytokine Response in Healthy Children

Type 1 diabetes (T1D) is considered to be a T-cell-mediated autoimmune disease in which genetic predisposition is affected by HLA class II alleles and polymorphisms in cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene. We tested the hypothesis whether these T1D-related gene polymorphisms modulate cytokine response and thus contribute to the development of autoimmunity. The study includes 67 non-diabetic children, typed for HLA class II alleles and CTLA-4 polymorphisms (+49A/G, CT60A/G, CTBC217_1C/T). We measured cytokine secretion of peripheral blood mononuclear cells after stimulation with tetanus toxoid (TT), polio virus, coxsackie virus B4, pertussis toxin (PT) and phytohemagglutinin (PHA). We saw higher IL-13 response to TT in individuals with DR3-DQ2 haplotype (P = 0.002). HLA class II protective haplotype, DR2-DQ6, showed association with increased production of IFN-gamma (P < 0.001) and IL-2 (P = 0.005) in response to polio virus. In children with the autoimmunity-related homozygous genotypes CTLA-4 +49G/G, CT60G/G and CTBC217_1T/T, we found enhanced PT- and PHA-induced IFN-gamma production (P < 0.05). The cytokine responses to studied antigens were weakly modified by HLA class II risk haplotypes, and children with T1D-associated HLA risk haplotypes are not specifically inclined to develop an immune response in general. Higher IFN-gamma and IL-2 response to enterovirus in children with HLA class II protective haplotype DR2-DQ6 could be of importance in the protection from T1D-associated enterovirus infections. All autoimmunity related CTLA-4 polymorphisms were associated with enhanced IFN-gamma. This suggests impaired downregulation of cellular immunity by these CTLA-4 polymorphisms.

Effect of Physical Activity on Cytokine Levels

PURPOSE: Acute exercise appears to modulate cytokine response. To date however no one has evaluated the effect of chronic level of activity on cytokine response. We evaluated the effect of average weekly level of moderate to vigorous activity on serum Interleuken-1β (IL-1β), IL-10, Tumor Necrosis Factor alpha (TNF-α) and the arachadonic acid metabolite, Lipoxin (LX) (which down-regulates neutrophilic response). METHODS: The subjects were comprised of 11 healthy individuals whose mean age, weight, height, and body mass index were 37.5±7 years, 157.3±31.9 pounds, 68.34±4.4 inches and 23.5±2.2 kg/m2, respectively. Subject activity level was recorded by accelerometry and categorized as mild, moderate, or vigorous. Blood was drawn after one week of recorded activity level and analyzed for cytokines. Statistical analysis included the Pearson correlation coefficients between level of activity and cytokine levels. RESULTS: A negative correlation (r) was seen between the cytokine levels and activity. The r values and the means and standard deviations for moderate to vigorous activity and cytokines are shown in table 1.TableCONCLUSION: While the results did not reach statistical significance, this small pilot study suggests a negative correlation between cytokine levels (IL-10, IL-1β, TNF-α, and LX) and moderate to vigorous activity. Larger studies are needed to further validate this finding. Support: SIU School of Medicine Central Research Committee

Anti-tumor action of tumor necrosis factor against Bomirski Ab melanoma in hamsters

Introduction:Tumor necrosis factor (TNF) is a cytokine able to exert anti-tumor activity in various models and modes of applications. However, the exact mechanism mediating the in vivo anti-tumor effect of TNF has not yet been clarified.Materials and Methods:The effects of intratumoral injection of rat TNF into hamsters bearing Bomirski Ab amelanotic melanoma, a fast growing tumor of high metastatic potential, were tested. Subcutaneous injections of the anti-angiogenic compound TNP-470 allowed analysis of its influence on the effects of TNF administration.Results:TNF application resulted in a significant inhibition of tumor growth and changes in metastasis pattern. Accelerated hemorrhagic necrosis was also observed, indicating the effect of the cytokine on tumor vessels. Moreover, the synergistic anti-tumor effect of TNF and anti-angiogenic agent TNP-470 suggested a cooperative activity of both substances on tumor vasculature. Microscopically, the effect of TNF injections was expressed by an increase in the amount of tumor cells with nuclear pyknosis and karryorrhexis. In vitro assays indicated a direct cytotoxic effect of TNF against Ab melanoma cells, most probably as an outcome of apoptosis. Intratumoral application of TNF also caused some modulation of cytokine response in melanoma-bearing hamsters as evidenced by increased levels of IL-6 in blood serum.Conclusions:This study established Bomirski Ab melanoma as a useful model for complex analysis of the anti-tumor activity of TNF.

Genes, diet and inflammatory bowel disease

Inflammatory bowel disease (IBD) arises in part from a genetic predisposition, through the inheritance of a number of contributory genetic polymorphisms. These variant forms of genes may be associated with an abnormal response to normal luminal bacteria. A consistent observation across most populations is that any of three polymorphisms of the Caspase-activated recruitment domain ( CARD15) gene are more prevalent in IBD patients as compared with unaffected controls. Similar aberrant responses to bacteria are associated with variants in Autophagy-related 16-like 1 ( ATG16L1) and human defensin ( HBD- 2, - 3 and - 4) genes. The defective bacterial signal in turn leads to an excessive immune response, presenting as chronic gut inflammation in susceptible individuals. Inconsistent population reports implicate the major histocompatability complex (MHC), that encodes a number of human leukocyte antigens ( HLA), MHC class I chain-related gene A ( MICA) or cytokines, such as tumour necrosis factor-alpha (TNF-α). Toll-like receptors encoded by the TLR4 or TLR9 genes may also play a role. Recent whole genome scans suggest that a rare variant in the interleukin-23 receptor ( IL23R) gene may actually protect against IBD. Other implicated genes may affect mucosal cell polarity (Drosophila discs large homologue 5, DLG5) or mucosal transporter function (sodium dependent organic cation transporters, SLC22A4 and SLC22A5). A variant in ABCB1 (ATP-binding cassette subfamily B member 1) may be especially associated with increased risk of UC. While pharmacogenetics is increasingly being used to predict and optimise clinical response to therapy, nutrigenetics may have even greater potential. In many cases, IBD can be controlled through prescribing an elemental diet, which appears to act through modulating cytokine response and changing the gut microbiota. More generally, no single group of dietary items is beneficial or detrimental to all patients, and elimination diets have been used to individualise dietary requirements. However, recognising the nature of the genes involved may suggest a more strategic approach. Pro- or prebiotics will directly influence the microbial flora, while immunonutrition, including omega-3 fatty acids and certain polyphenols, may reduce the symptoms of gut inflammation. The expression of gut transporters may be modulated through various herbal remedies including green tea polyphenols. Such approaches would require that the gene of interest is functioning normally, other than its expression being up or down-regulated. However, new approaches are being developed to overcome the effects of polymorphisms that affect the function of a gene. A combination of human correlation studies with experimental models could provide a rational strategy for optimising nutrigenetic approaches to IBD.

Cytokine and chemokine responses after exposure to ionizing radiation: Implications for the astronauts

For individuals traveling in space, exposure to space radiation is unavoidable. Since adequate shielding against radiation exposure is not practical, other strategies for protecting the astronauts must be developed. Radiation is also an important therapeutic and diagnostic tool, and evidence from the clinical and experimental settings now shows a firm connection between radiation exposure and changes in cytokine and chemokine levels. These small proteins can be pro- or anti-inflammatory in nature and the balance between those two effects can be altered easily because of exogenous stresses such as radiation. The challenge to identify a common perpetrator, however, lies in the fact that the cytokines that are produced vary based on radiation dose, type of radiation, and the cell types that are exposed. Based on current knowledge, special treatments have successfully been designed by implementing administration of proteins, antibodies, and drugs that counteract some of the harmful effects of radiation. Although these treatments show promising results in animal studies, it has been difficult to transfer those practices to the human situation. Further understanding of the mechanisms by which cytokines are triggered through radiation exposure and how those proteins interact with one another may permit the generation of novel strategies for radiation protection from the damaging effects of radiation. Here, we review evidence for the connection between cytokines and the radiation response and speculate on strategies by which modulating cytokine responses may protect astronauts against the detrimental effects of ionizing radiations.