Reduction In Interleukin-2 Production Research Articles

The Effect of Interleukin-2 -330 T/G Polymorphism in People with Schizophrenia Among The Batak and Javanese Ethnic Groups.

Schizophrenia is a complex disorder involving multiple genes with mild to moderate effects and non-genetic risk factors such as environmental and psychological influences that alter brain chemistry. Significant reduction in interleukin-2 production by peripheral lymphocytes is an immunological finding replicated in schizophrenia across various countries. Investigations on the interleukin-2 -330 T/G polymorphism in people with schizophrenia (PWS) are still minimal, and the study location involves only a few countries with different results. Therefore, this study aims to examine the effect of interleukin-2 -330 T/G polymorphisms in people with schizophrenia among the Batak and Javanese ethnic groups in Indonesia, particularly in North Sumatra. This study used purposive non-probability sampling to recruit people with schizophrenia with 120 Batak and 120 Javanese subjects who were hospitalized at Prof. M. Ildrem Mental Hospital, Medan, Indonesia. The interleukin-2 -330 T/G polymorphism was examined by the PCR method. The results showed that the genotype frequency of the Batak people with schizophrenia is as follows: GG 11.7%, TG 53.3% and TT 35%. Furthermore, the group of Javanese people with schizophrenia is as follows: GG 23.3%, TG 44.2% and TT 32.5%. The OR for the genotypic comparison of GG was found to be 2.154 with 95% CI 0.992-4.678, p=0.053, while that of the TG genotype was 0.892 with 95% CI 0.505-1.574 and p=0.693. The T allele was higher than the G allele in Batak and Javanese ethnic groups, as demonstrated by p=0.713, OR=0.919 with 95% CI 0.641-1.318. There is no statistically significant difference between the occurrence frequency of alleles. In addition, there is no significant relationship between the GG and the TG genotype of the interleukin-2 - 330T/G polymorphism in people with schizophrenia among the Batak and the Javanese ethnic groups.

Suppression of the allogeneic response by the anti‐allergy drug N‐(3,4‐dimethoxycinnamonyl) anthranilic acid results from T‐cell cycle arrest

Previously we have shown that indoleamine 2,3-dioxygenase (IDO) and the tryptophan metabolite, 3-hydroxykynurenine (3HK) can prolong corneal allograft survival. IDO modulates the immune response by depletion of the essential amino acid tryptophan by breakdown to kynurenines, which themselves act directly on T lymphocytes. The tryptophan metabolite analogue N-(3,4-dimethoxycinnamonyl) anthranilic acid (DAA, 'Tranilast') shares the anthranilic acid core with 3HK. Systemic administration of DAA to mice receiving a fully MHC-mismatched allograft of cornea or skin resulted in significant delay in rejection (median survival of controls 12 days, 13 days for cornea and skin grafts, respectively, and of treated mice 24 days (P < 0.0001) and 17 days (P < 0.03), respectively). We provide evidence that DAA-induced suppression of the allogeneic response, in contrast to that induced by tryptophan metabolites, was a result of cell cycle arrest rather than T-cell death. Cell cycle arrest was mediated by up-regulation of the cell cycle-specific inhibitors p21 and p15, and associated with a significant reduction in interleukin-2 production, allowing us to characterize a novel mechanism for DAA-induced T-cell anergy. Currently licensed as an anti-allergy drug, the oral bioavailability and safe therapeutic profile of DAA make it a candidate for the prevention of rejection of transplanted cornea and other tissues.

Cytokine-Mediated Programmed Proliferation of Virus-Specific CD8+ Memory T Cells

During infection, CD8(+) Tcells not only respond to antigenic signals through their Tcell receptor (TCR) but also incorporate inflammatory signals from cytokines produced in the local infected microenvironment. Transient TCR-mediated stimulation will result in programmed proliferation that continues despite removal of the antigenic stimulus, but it remains unclear whether brief exposure to specific cytokines will elicit similar effects. Here, we have demonstrated that brief stimulation of memory Tcells with interleukin-12 (IL-12) and interleukin-18 (IL-18) results in tightly regulated programmed proliferation, in addition to acquisition of enhanced virus-specific cytokine production and cytolytic activity. CD8(+) Tcells briefly exposed to IL-12 and IL-18 invitro showed improved antiviral activity invivo, as demonstrated by increased proliferation and reduced viremia. These results indicate that even transitory exposure to inflammatory cytokines can provide a selective advantage to infiltrating CD8(+) Tcells by triggering a developmental program that is initiated prior to direct contact with virus-infected cells.

Ursolic acid inhibits T-cell activation through modulating nuclear factor-κ B signaling

To investigate the effects of ursolic acid (UA) on T-cell proliferation and activation, as well as to examine its effect on nuclear factor-κB (NF-κB) signaling pathway in T cells. T-cells isolated from BALB/c mice were incubated with UA at concentrations ranging from 5-30 μmol/L in the presence of phorbol 12-myristate 13-acetate (PMA) or PMA plus ionomycin. The proliferation of T cells was measured by the MTT assay. The expressions of CD69, CD25, and CD71 on T-cell surface were analyzed using flow cytometry. The level of interleukin-2 (IL-2) in the culture supernatant of activated T cells was quantified by enzyme-linked immunosorbent assay (ELISA). The level of phosphorylated IκB-α (p-IκB-α) in total protein and p65, a subunit of NF-κB, nuclear translocation were measured by Western blot analysis. UA in a dose-dependent manner significantly decreased the proliferation and inhibited the surface expressions of CD69, CD25, and CD71 in murine T lymphocytes upon in vitro activation (P<0.01). Significant reduction of IL-2 production was found in activated T cells treated with UA (P<0.01). The PMA-induced increase in p-IκB-α protein was inhibited, and nuclear translocation of p65 from the cytoplasm was blocked by UA. UA is a potent inhibitor for T cell activation and proliferation; these effects are associated with the inhibition of NF-κB signaling pathway.

Direct influence of mild hypothermia on cytokine expression and release in cultures of human peripheral blood mononuclear cells.

Hypothermia is associated with elevated frequency of infectious complications. Dysfunction of the immune response caused by hypothermia has been demonstrated in both clinical and animal studies, but it still remains unclear to what extent immunocompetent cells are directly influenced by hypothermia. To estimate the direct influence of mild hypothermia on cytokine expression and release by human peripheral blood mononuclear cells (PBMC), primary cultures of PBMC were incubated at 34 degrees C or 32 degrees C activated by lipopolysaccharide (LPS), phytohemagglutinin (PHA), or tumor necrosis factor-alpha (TNF-alpha). The cytokine gene expression was evaluated by RT-PCR. Release of interleukin-2 (IL-2), IL-6, IL-10, and TNF-alpha was measured by ELISA. Mild hyperthermia significantly impaired IL-2 gene expression in PHA-stimulated cultures of PBMC and decreased IL-2 release in all variants of cultures. Secretion of IL-6, IL-10, and TNF-alpha was decreased in hypothermic cultures of PBMC stimulated with the T lymphocyte activator PHA. Slight suppression of IL-10 secretion was observed also in TNF-alpha-stimulated hypothermic cultures of PBMC. TNF-alpha release increased slightly in mild hypothermia control cultures. Our data demonstrate that the direct influence of hypothermia on cytokine expression and release from PBMC is not uniform. Reduction of IL-2 production might play a crucial role in the impairment of immune response in hypothermia.

Defective survival and activation of thymocytes in transgenic mice expressing a catalytically inactive form of Ca2+/calmodulin-dependent protein kinase IV.

We have generated transgenic mice that express a catalytically inactive form of Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) specifically in thymic T cells. The presence of this protein results in a markedly reduced thymic cellularity, although the distribution of the remaining cells is normal based on evaluation of the CD4 and CD8 cell surface antigens that are used to gauge T cell development. Isolated thymic T cells from the transgenic mice also show a dramatically decreased survival rate when evaluated in culture under conditions that do not favor activation. When challenged with an activating stimulus such as alpha-CD3 or a combination of phorbol ester plus ionophore, the cells are severely compromised in their ability to produce the cytokine interleukin-2 (IL-2). Reduction of IL-2 production is secondary to the inability to phosphorylate the cAMP response element binding protein, CREB, and induce expression of the immediate early genes such as Fos B that are required to transactivate the IL-2 promoter. Because transgene expression was regulated by the proximal promoter of the murine lck gene and this promoter is inactivated in T cells that exit the thymus, the mutant hCaMKIV is not present in peripheral T cells. Consequently, T lymphocytes present in the spleen can be activated normally in response to either stimulus mentioned above, demonstrating that the effects of the inactive CaMKIV on activation are reversible. Our results suggest that CaMKIV may represent a physiologically relevant CREB kinase in T cells and that the enzyme is also required to ensure normal expansion of T cells in the thymus. Whereas the pathway responsible for this latter role is yet to be elucidated, it is unlikely to include CREB phosphorylation.

Nitric oxide increased interleukin-4 expression in T lymphocytes.

Nitric oxide (NO) is a regulator of many biological functions including T helper 1 (Th1)/T helper 2 cells balance. It has been demonstrated that NO inhibits the secretion of interleukin-2 (IL-2) and interferon-gamma on Th1 cells. Here we showed that, in addition to the suppression of IL-2 production, NO-generating agents sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) increased the secretion of IL-4 both in Th2 clones and EL4 T cells. The additive effect was dependent on the dose of SNP and SNAP. Augmentation of IL-4 production was detected with 1 microM SNP, and up to threefold increase in IL-4 secretion could be observed with higher concentrations of SNP/SNAP. NO also weakly increased the activation of IL-4 promoter. In contrast, NO markedly inhibited the induction of IL-2 promoter, which could account for most of the reduction in IL-2 production. Analysis of the transcriptional elements on IL-2 and IL-4 promoters revealed a selective inactivation of NF-kappa B and NF-AT. It is suggested that despite the complex feedback network regulating NO production, the enhanced IL-4 expression would lead to the expansion of Th2 cells once NO is generated.

Alteration of interleukin-2 (IL-2) and soluble IL-2 receptor secretion in the sera and urine of patients with rickettsial boutonneuse fever.

Sera and urine samples from 115 Sicilian patients with boutonneuse fever (BF), obtained at the time of diagnosis and after clinical recovery, were analyzed for concentrations of interleukin (IL)-2 and soluble IL-2 receptor (sIL-2R). There were significantly high levels of sIL-2R in the urine and sera of patients with acute BF compared with healthy controls, and the values returned to normal following successful chemotherapy. The data indicate that the sIL-2R urine concentrations correlated directly with the sIL-2R sera levels. In contrast, in all tested sera and urine samples, IL-2 levels were normal. Furthermore, a reduction in IL-2 production by peripheral blood mononuclear cells from acute BF patients was also observed. sIL-2R represents an unspecific marker useful to monitor the evolution of BF.

The role of experimental chronic renal failure and aluminium intoxication in cellular immune response

A positive correlation between successful kidney transplantation, few rejection episodes, greater susceptibility to infection and morbidity in patients with high tissue levels of aluminium (Al) indicate that the metal may play a role in the immune response. The aim of this study was to determine if experimental aluminium intoxication could result in significant changes in lymphocyte activity in uraemic and nonuraemic rats. Lewis rats were divided into four groups: normals (N), nephrectomized control (U), and Al-treated (N + Al) and nephrectomized Al-treated (U + Al), which received a cumulative dose of 30 mg Al over a 4-week period. Al quantification, histology, histochemical analysis and immunological assays were performed after Al intoxication. High tissue levels of Al and positive histochemical staining in bones were seen in Al-treated rats. Bone histology revealed osteomalacia in U + Al rats. No statistical differences were observed in mixed lymphocyte cultures from controls and Al-treated rats, whereas U and Al-treated rats showed a decrease in lymphoproliferative response to mitogen and natural killer cell cytotoxic activity. A decreased helper T lymphocyte: cytotoxic T lymphocyte cell ratio and a reduction in interleukin-2 production were observed only in the U + Al group. A reduced number of total T lymphocytes was detected in the spleens of all Al-treated rats. These findings suggest that aluminium toxicity may contribute to immunological impairment in chronic renal failure.

Decreased interleukin-2 production in murine acute pancreatitis: Potential for immunomodulation

BACKGROUND & AIMS: The role of the cytokine interleukin 2 (IL-2) has long been recognized as central to normal immunologic function and defense against infection after burns and trauma, but little effort has been directed towards its role in acute pancreatitis (AP), which also has a high mortality related to sepsis. This study investigated the potential role of IL-2 in mice with diet-induced AP. METHODS: AP was induced in mice by 10 days of feeding a choline-deficient, ethionine- supplemented diet. T-helper (CD4) cells were estimated, and T-cell mitogen-stimulated splenocyte proliferation and IL-2 production in vitro were measured on days 3, 7, and 10. RESULTS: Significant reduction in IL-2 production was found on day 3 (32%; P < 0.05) and day 10 (48%; P < 0.005). Administration of intraperitoneal lipopolysaccharide on day 10 was associated with reduced IL-2 production (P < 0.025) 4 hours later and 90% mortality in animals with AP. In vivo therapy with recombinant IL-2 improved in vitro IL-2 secretion (P < 0.05) and reduced lipopolysaccharide-induced mortality (P = 0.036). CONCLUSIONS: Murine diet-induced AP is associated with impaired immune function and increased susceptibility to sepsis and may be a valuable tool in the investigation of immunomodulation in AP. (Gastroenterology 1996 Feb;110(2):583-8)

Abnormal T-cell function in patients with psoriatic arthritis: evidence for decreased interleukin 2 production.

Psoriatic arthritis (PSA) is an inflammatory arthritis associated with psoriasis. Although not considered an autoimmune process, there is evidence for humoral and cellular immune abnormalities similar to autoimmune diseases such as rheumatoid arthritis and systemic lupus (SLE). We investigated mitogen-induced proliferation and interleukin 2 (IL-2) production by peripheral blood mononuclear cells in patients with PSA. Both IL-2 production and proliferation were significantly decreased in PSA patients when compared to controls. Increased arachidonic acid metabolism has been reported in skin and peripheral mononuclear cells of patients with psoriasis and PSA. We therefore also investigated the effect of indomethacin and prostaglandin E2 (PGE2) on IL-2 production. Addition of indomethacin to cultures did not significantly change IL-2 production in patients with PSA, but did so in controls. PGE2 produced a significant reduction in IL-2 production in PSA and in controls.

Nitric oxide modulates lymphocyte proliferation but not secretion of IL-2.

The objective of this study was to determine the effects of nitric oxide (NO) on lymphocyte proliferation and cytokine release. Bronchoalveolar lavage (BAL) cells served as the source of NO and were obtained from rats treated with a single, intratracheal dose of bleomycin (3.6 mg/kg). At the time of sacrifice, the spleens were removed and the lymphocytes separated. Co-cultures containing BAL cells, lymphocytes and concanavalin-A were established and incubated at 37 degrees C for 24 hours at which time proliferation, nitrite concentration and interleukin-2 (IL-2) production were measured. At ratios from 5:1 to 1:4 (BAL:lymphocyte) there was a significant reduction in lymphocyte proliferation. There was a significant, negative correlation between NO concentration and thymidine incorporation which was reversed when the NO synthase inhibitor NG-monomethyl-L-arginine (NMA) was added to the co-cultures. Despite marked inhibition of spleen lymphocyte proliferation by NO, released by BAL cells, there was no corresponding reduction in IL-2 production. These data demonstrate that macrophages, activated in vivo, produce NO which regulates lymphocyte growth but not necessarily functions such as the secretion of the cytokine IL-2. Further, the ability of IL-2-dependent CTLL-2 cells to proliferate in the presence of excess IL-2 was also inhibited by BAL cells, confirming that NO inhibits lymphocyte growth.

Interleukin 2 production and its relationship with T lymphocyte subsets in patients with obstructive jaundice

Sepsis remains a major risk in the high mortality and morbidity after surgery for obstructive jaundice. The reasons for the increased susceptibility to infection are unknown. This study examined interleukin 2 (IL-2) production and the lymphocyte response to PHA mitogen in 31 patients with obstructive jaundice. Among them, 18 patients were simultaneously investigated by enumeration of T lymphocyte subsets in peripheral blood with APAAP technique. The results showed that the patients had significantly decreased IL-2 production and lymphocyte response to PHA mitogen. The percentage of Leu 3a (helper/inducer T cell) in the patients was significantly lower than that in normal controls. Leu 3a/Leu 2a (suppressor/cytotoxic T cell) ratio was significantly lower in these patients. The reduction of IL-2 production correlated significantly with the suppression of lymphocyte proliferation but not with the percentage of Leu 3a cells. From these results, it may be suggested that the reduction of IL-2 production in the patients with obstructive jaundice is an important reason for the suppression of T lymphocyte proliferative response, not merely a reflection of the decrease of helper T cells.

Immune alterations induced by a conditioned aversive stimulus: Evidence for a time-dependent effect

This study investigated the immune alterations induced in rats by an aversive conditioned stimulus (CS), which had been developed through pairings with electric shock. The results showed that the CS induced pronounced alterations of splenic lymphocyte function as indicated by a reduction in the mitogenic responsiveness to the T-cell mitogens concanavalin-A (Con-A) and phytohemag-glutinin (PHA) and the B-cell mitogen lipopolysaccharide (LPS), a reduction in interleukin-2 production, and a reduction in natural-killer-cell activity. The magnitude of the immune alterations was dependent on the time interval between the training and testing of the CS. There was little evidence of an immunomodulatory effect of the CS 1 day following training, but the effect developed as the interval between training and test was extended (3, 6, and 12 days). In contrast, a mitogen-stimulation assay using blood lymphocytes showed a reduction in the mitogenic responsiveness to Con-A and PHA that was comparable across the days following training. These results establish a time-dependent, compartment-specific, CS-induced immunomodulatory effect.