Biomedical subjects

M Kurimoto

Publications and source records attributed to M Kurimoto.

At least 73 records · Page 4Linked to original sources

PubMed2000

Differential effects of N-acetyl-l-cysteine on IL-2- vs IL-12-driven proliferation of a T cell clone: implications for distinct signalling pathways.

Using a T cell clone (2D6) capable of responding to IL-2 and IL-12, we compared the effects of NAC on IL-2 and IL-12-driven T cell proliferation. Addition of N-acetylcysteine (NAC) to 2D6 cultures did not affect IL-2 stimulated proliferation, but strikingly inhibited IL-12 stimulated proliferation. These differential NAC effects did not correlate with the patterns of the mitogen-activated protein kinase (MAPK) activation following cytokine stimulation and its regulation by NAC. Although a p38 MAPK inhibitor downregulated both IL-2- and IL-12-induced proliferation, this effect was seen at drug concentrations one order higher than those reportedly used to specifically inhibit p38 MAPK. The results suggest the existence of distinct signalling pathways and a common, indispensable signalling molecule in IL-2- and IL-12 driven T cell proliferation.

Acetylcysteine↗

PubMed2000

Increased concentrations of plasma IL-18 in patients with hepatic dysfunction after hepatectomy.

We investigated the dynamic aspects of circulatory IL-18 and other inflammatory cytokines in patients who underwent a hepatectomy. In patients with post-operative hepatic dysfunction, plasma concentrations of these cytokines increased, reflecting severe surgical trauma. IL-6, IL-10 and IFN-gamma increased in the early phase, while IL-18 increased in the later phase after 1 week. Interestingly, the increase in the plasma IL-18 concentration was correlated with that in serum bilirubin levels in hepatectomized patients. Hence, the decrease in the hepatic metabolism of IL-18 may cause the plasma accumulation of IL-18. This mechanism was confirmed using rat experiments. Intravenously administered human IL-18 was excreted into bile. Furthermore, the plasma clearance of human IL-18 was prolonged in bile duct-ligated rats. These results suggest that IL-18 is metabolized in the liver and excreted into bile, and an increase in plasma IL-18 in patients with hepatic dysfunction reflects the decreased metabolism in the liver.

Adult↗

PubMed2000

Lipopolysaccharide/endotoxin induces IL-18 via CD14 in human peripheral blood mononuclear cells in vitro.

IL-18 shares activities with IL-12 in generating T-helper 1 cells and cytokine response. It mediates LPS/endotoxin lethality by IL-12 independent interferon-gamma synthesis and it induces bacteria-related organ failure. As peripheral blood mononuclear cells (PBMC) are potent producers of IL-18, we studied the regulation of IL-18 upon exposure to LPS and Staphylococcus aureus (SAC) in vitro. Freshly isolated PBMC constitutively expressed IL-18 mRNA. After unstimulated preincubation for 48 h, however, IL-18 transcripts were nearly not detectable by RT-PCR, but inducible by LPS or SAC (P<0.01). Both LPS and SAC were potent stimuli of IL-18 protein secretion (P<0.01). LPS-mediated IL-18 gene expression and secretion was CD14-dependent and significantly inhibited by co-incubation of PBMC with neutralizing CD14 antibody (P<0.01). We conclude that LPS-driven IL-18 is dependent on the expression of costimulatory factors and that IL-18 inhibition might attenuate IL-18-related toxic effects.

Adult↗

PubMed2000

Effect of interleukin-18 on viral myocarditis: enhancement of interferon- gamma and natural killer cell activity.

Encephalomyocarditis virus causes viral myocarditis with myocyte necrosis and inflammatory cell infiltration in mice. Because previous studies have shown that some cytokines prevent the sequelae of myocarditis, we assessed the effect of a newly identified cytokine, interleukin-18 (IL-18), in preventing the sequelae of myocarditis. Murine IL-18 (10 microg/day/mouse) was given peritoneally for 10 days in C3H mice infected with EMC virus. Mice were divided into group IL-18 (infected-treated), saline group (infected-untreated), group IL-18-2 (treatment started on day 2), group IL-18-5 (treatment started on day 5). Although the 14-day survival rate in saline group was 20%, that in the group IL-18 increased to 80% (P<0.05). Either mice in group IL-18-2 or in group IL-18-5 did not survive longer than saline group. The viral titer of the heart on day 3 was lower in group IL-18 compared to the saline group (1.00+/-0.20 log(10)tissue culture infected dose (TCID)(50)/mg wet weight v 1.42+/-0.12 log(10)TCID(50)/mg, n=3 of each). Mice in group IL-18 had less myocardial necrosis and cellular infiltration than the saline group. The myocardial expression of interferon- gamma (IFN- gamma) mRNA in group IL-18 was significantly (P<0.05) greater than the saline group on days 1 and 3 after viral inoculation. Circulating IFN- gamma was significantly elevated on days 1, 5, and 7, but significantly reduced on day 3. The natural killer cell activities in the spleen on days 1, 3, and 5 were significantly (P<0.05) greater in group IL-18 than in the saline group (41+/-9%v 10+/-6% on day 3, 4 of each). We conclude that IL-18 reduces the severity of EMC viral myocarditis by inducing cardiac expression of IFN- gamma mRNA and increasing splenic natural killer cell activity.

Animals↗

PubMed2000

Induction of the activity of the histamine-forming enzyme, histidine decarboxylase, in mice by IL-18 and by IL-18 plus IL-12.

OBJECTIVE AND DESIGN: IL-18 shares functional properties with IL-12, which induces an elevation of histidine decarboxylase (HDC) activity in mouse tissues. Therefore, we examined the effects of IL-18 and IL-18+IL-12 on HDC activity. METHODS: IL-18, IL-12 or IL-18+IL-12 was intraperitoneally injected into BALB/c and C3H/HeN mice and their HDC activities were measured. RESULTS: IL-18, at effective antitumour doses, induced HDC activity in lung, liver, spleen and bone. The IL-18-induced HDC elevation was more rapid than that induced by IL-12. As with IL-12, repeated injections of IL-18 produced more HDC activity than a single injection. Repeated injections of IL-18+IL-12 induced serious illness and produced marked HDC activity. However, an inhibitor of HDC did not prevent the illness. CONCLUSIONS: IL-18 may be involved in the stimulation of histamine synthesis during the course of immune responses, though an elevation of HDC activity is not itself the direct cause of the serious illness induced by IL-18+IL-12.

Animals↗

PubMed2000

Elevation of serum interleukin-18 levels and activation of Kupffer cells in biliary atresia.

BACKGROUND/PURPOSE: Interleukin-18 (IL-18)/interferon-gamma-inducing factor (IGIF) is a novel proinflammatory cytokine that can induce interferon gamma (IFN-gamma). In addition, IL-18 enhances intracellular adhesion molecule-1 (ICAM-1) expression as well as Fas ligand (FasL) expression, and induces apoptosis in hepatic injury. The aim of this study was to clarify the potential role of IL-18 in the pathogenesis of the progressive inflammation and fibrosis in biliary atresia (BA). METHODS: Six children with BA before hepatic portoenterostomy (HPE), 13 with BA including 7 without jaundice and 6 with persistent jaundice after HPE, and 16 healthy controls were examined. Blood samples were obtained preoperatively from 6 patients, after HPE from 13, and after liver transplantation from 4. The IL-18 level was determined by an enzyme-linked immunosorbent assay (ELISA). Immunohistochemically, liver specimens from BA patients were studied using a monoclonal antibody to macrophage-associated antigen (CD68). RESULTS: IL-18 levels were elevated in the patients before HPE compared with those of the controls (349+/-54 pg/mL v. 138+/-13 pg/mL, P<.0001). After HPE, extremely high concentrations of IL-18 were observed in patients with persistent jaundice (532+/-95 pg/mL, P<.0001), and the IL-18 levels were significantly high even in the patients without jaundice (249+/-29 pg/mL, P<0.005). The high IL-18 level lasted for a long time even in the patients without jaundice after HPE. In contrast, the IL-18 levels immediately decreased after liver transplantation. Immunohistochemically, the number of CD68-positive Kupffer cells was significantly higher, and the size was larger in the livers of the patients than in the controls. The proliferation of CD68-positive cells was much more conspicuous in the liver specimens obtained during liver transplantation than in those at the time of HPE. CONCLUSIONS: Our findings showed elevation of serum IL-18 levels and activation of Kupffer cells in BA. IL-18 released from activated Kupffer cells might play an important role in the pathophysiology of the progressive inflammation and fibrosis in BA. Furthermore, IL-18 level may be related to the prognosis in patients with BA.

Antigens, CD↗

PubMed2000

Polygonum tinctorium extract suppresses nitric oxide production by activated macrophages through inhibiting inducible nitric oxide synthase expression.

Despite its beneficial role in host defense mechanisms, excessive nitric oxide (NO) production by activated macrophages has been implicated in several inflammatory diseases. To clarify the mechanisms of anti-inflammatory activities of Polygonum tinctorium, we evaluated whether extracts of P. tinctorium could modulate the production of NO by activated macrophages. An AcOEt extract of P. tinctorium markedly inhibited NO synthesis by interferon-gamma (IFN-gamma)/lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages and the macrophage-like cell line RAW 264.7 in a dose-dependent manner. Inhibition of NO synthesis was achieved by reducing inducible NO synthase (iNOS) expression at protein and mRNA levels. However, the AcOEt extract of P. tinctorium failed to inhibit NO synthesis when iNOS was already expressed following stimulation with IFN-gamma and LPS. The AcOEt extract also exhibited inhibitory activity on iNOS expression in human lung epithelial A549 cells stimulated with a combination of IFN-gamma, TNF-alpha and IL-1 beta without affecting the expression of constitutive isoforms of NOS. Furthermore, in vivo injection of the AcOEt extract of P. tinctorium into LPS-treated mice significantly reduced NO synthesis by peritoneal exudate cells under ex vivo conditions. These results suggest that P. tinctorium extract may be a potential therapeutic modulator of NO synthesis in various pathological conditions.

Animals↗

PubMed2000

Deficient Th1-type immune responses via impaired CD28 signaling in ultraviolet B-induced systemic immunosuppression and the restorative effect of IL-12.

A single large dose (15 kJ/m(2)) of UVB-irradiation induces systemic immunosuppression and tolerance. We previously reported that IL-12 promotes the accessory cell function of epidermal Langerhans cells. In this study we have examined whether IL-12-pretreated antigen-presenting cells (APC) could restore the diminished T-cell response in mice irradiated with a single large dose of UVB. Spleen cells from UVB-irradiated mice showed reduced IFN-gamma production in a hapten-specific response but the function of APC in non-exposed skin of UVB-irradiated mice was not impaired. The pretreatment of APC with IL-12 did not restore the impaired IFN-gamma production by T cells from UVB-irradiated mice. Neither IL-10 nor TGF-beta was found to be involved in the suppression. Instead, we observed that anti-CD3 mAb-induced IFN-gamma production by T cells from UVB-irradiated mice was not augmented in the presence of anti-CD28 mAb, whereas IL-4 production was enhanced by the addition of anti-CD28 mAb. Furthermore, the reduced IFN-gamma production by T cells from UVB-irradiated mice in response to antigen plus APC could be restored by adding IL-12 to the culture. Our results thus indicate that UVB-induced systemic immunosuppression involves impaired Th1-type responses of T lymphocytes through CD28 stimulation, and that IL-12 compensates for the impaired CD28 costimulatory signaling in T cells resulting in the restoration of Th1-type responses.

Animals↗

PubMed2000

Tissue factor and cancer procoagulant expressed by glioma cells participate in their thrombin-mediated proliferation.

The relationship between coagulation cascade activation and glioma cell proliferation was examined. The human glioma cell lines T98G, TM-1 and normal human astrocyte cell strain (NHA) were examined. Using anti-tissue factor (TF) antibody, immunocytochemical detection of TF antigen was obtained in both cell lines and cell strain. TF antigen in cell lysates was also measured by enzyme linked immunosorbent assay (ELISA). In a one-stage clotting assay, T98G, TM-1 and NHA revealed procoagulant activity (PCA) in normal human plasma and factor VII deficient plasma. PCA in normal human plasma was significantly inhibited by both inhibitory anti-TF antibody and cysteine protease inhibitor HgCl2. This result indicates that T98G, TM-1 and NHA cells express not only TF but also cancer procoagulant (CP) at the same time. In a cell proliferation assay, thrombin induced proliferation in T98G and TM-1 cells in a dose-dependent fashion and in NHA cell in a bell-shaped fashion. This mitogenic stimulant was inhibited by the specific thrombin inhibitor hirudin. The combinations of coagulation factors II, V, and X with or without factor VII induced proliferation in T98G, TM-1, and NHA cells. The maximal mitogenic stimulatory effects were larger in glioma cells than in NHA. These mitogenic stimulatory effects were also inhibited by hirudin. Each coagulation factor on its own or in any other combination of coagulation factors had no proliferative effect. Thus, these mitogenic stimulatory effects were considered to be the effect of thrombin. In conclusion, T98G and TM-1 human glioma cells express two different types of procoagulants TF and CP. In the presence of coagulation factors, these glioma cells can generate thrombin and this thrombin generation is capable of inducing glioma cell proliferation in vitro.

Antibodies↗

PubMed2000

Effectiveness of cancer vaccine therapy using cells transduced with the interleukin-12 gene combined with systemic interleukin-18 administration.

We introduced the interleukin-12 (IL-12) gene into mouse renal cell carcinoma (RenCa) cells to develop a tumor vaccine and to examine mechanisms of tumor rejection. IL-12-secreting RenCa (RenCa/IL-12) cells were completely rejected when implanted into syngeneic BALB/c but not athymic nude mice, suggesting that T cells were involved in this antitumor effect. Depletion of natural killer (NK) cells in nude mice did not affect the tumor growth of RenCa/IL-12. The simultaneous injection of mitomycin C-treated RenCa/IL-12 inhibited the tumor growth of parental RenCa injected at a distant site, whereas injection of mitomycin C-treated parental RenCa did not. The antitumor effect of RenCa/IL-12 as a cancer vaccine was induced by CD8+ T cells and NK cells and was inhibited by CD4+ T cells. Although the systemic administration of recombinant IL-18 (rIL-18) alone did not inhibit the tumor growth, it did enhance the cancer vaccine effect of RenCa/IL-12. The combination therapy of RenCa/IL-12 and the systemic administration of rIL-18 retarded even the growth of established tumors. The effector cells of this combination therapy consist not only of CD8+ T cells and NK cells but also of CD4+ T cells. This synergistic cancer vaccine effect of in situ secretion of IL-12 and the systemic administration of rIL-18 may be attributed to a functional change of CD4+ T cells.

Animals↗

PubMed2000

Expression and responsiveness of human interleukin-18 receptor (IL-18R) on hematopoietic cell lines.

Interleukin-18 (IL-18) is a new inflammatory cytokine sharing biological functions with IL-12. The human IL-18 receptor (IL-18R) was recently identified and was found to be expressed on normal peripheral blood lymphocytes. To further characterize IL-18R, we analyzed IL-18R expression using a series of human hematopoietic cell lines selected from various cell lineages. We found the IL-18R expression on cells of T and B lineages as expected from analysis on normal cells. The IL-18R expression, however, was found not to be restricted to any specific maturation stages of T and B cells. In addition, we detected IL-18R expression in myeloid, monocytoid, erythroid and megakaryocytic cell lines, indicating that normal counterparts of these cell lineages could express IL-18R and participate in in vivo reactions caused by IL-18. Biochemical studies showed that IL-18R proteins exist as heterogeneous molecules ranging from 60 to 110 kDa. Deglycosylation experiments indicated that the heterogeneity could not be explained only by a difference in glycosylation. We also found that tumor necrosis factor-alpha (TNF-alpha) modulated the IL-18R expression, which implies an important in vivo effect of TNF-alpha on IL-18-induced reaction. Analyzing the responsiveness of IL-18R, we found that only KG-1 responded to IL-18 stimulation. This suggests that certain inhibitory mechanisms of IL-18 responsive genes are involved in the all IL-18R-positive cell lines except KG-1.

B-Lymphocytes↗

PubMed2000

Serum interferon-gamma-inducing factor/IL-18 levels in primary biliary cirrhosis.

Primary biliary cirrhosis is an autoimmune disease of the liver in which T helper 1 cytokines predominate over those of T helper 2 in the pathogenesis. Interleukin- 18 (IL-18), for which the gene was recently cloned, is a novel T helper 1 cytokine, which augments interferon-gamma production. We designed this study to clarify the role of IL-18 in primary biliary cirrhosis and to examine whether serum IL-18 level can be a prognostic indicator for the disease. Serum IL-18 levels were measured using an enzyme linked immuno sorbent assay with mouse monoclonal antibodies. Twenty-two healthy volunteers, 31 patients with primary biliary cirrhosis (Scheuer's stage I, 13; II, 10; and IV, 8), 20 patients with autoimmune hepatitis, 11 patients with virus-related liver cirrhosis and six patients with obstructive jaundice were enrolled. Significant differences of serum IL-18 levels were observed between patients with Scheuer's stage IV and those with stage I, or II, virus-related liver cirrhosis and obstructive jaundice (P < 0.05). The IL-18 levels in primary biliary cirrhosis increased according to the disease progression, and fell promptly after living-related liver transplantation. Moreover, serum IL-18 levels in primary biliary cirrhosis were correlated with serum bilirubin concentrations and the Risk scores of the Mayo Clinic prognostic model for the disease. The IL-18 levels observed in patients with autoimmune hepatitis were also elevated, and correlated with the activity of the disease. These results indicate that serum interleukin-18 levels reflect the severity of primary biliary cirrhosis, the activity of autoimmune hepatitis, and may be an additive prognostic indicator in primary biliary cirrhosis.

Autoimmune Diseases↗

PubMed2000

Renal carcinogenesis induced by ferric nitrilotriacetate in mice, and protection from it by Brazilian propolis and artepillin C.

The protective effect of Brazilian propolis and its extract Artepillin C against ferric nitrilotriacetate (Fe-NTA)-induced renal lipid peroxidation and carcinogenesis was studied in male ddY mice. Fe-NTA-induced renal lipid peroxidation leads to a high incidence of renal cell carcinoma (RCC) in mice. Administration of propolis by gastric intubation 2 h before or Artepillin C at either the same time, 2 h, or 5 h before the intraperitoneal injection of Fe-NTA (7 mg Fe/kg) effectively inhibited renal lipid peroxidation. This was evaluated from the measurement of renal thiobarbituric acid-reactive substances (TBARS) or histochemical findings of 4-hydroxy-2-nonenal (4-HNE)-modified proteins and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Repeated injection of Fe-NTA (10 mg Fe/kg per day, twice a week for a total of 16 times in 8 weeks) caused subacute nephrotoxicity as revealed by necrosis and pleomorphic large nuclear cells in the renal proximal tubules, and gave rise to RCC 12 months later. A protective effect from carcinogenicity was observed in mice given propolis or Artepillin C. Furthermore, the mice given Fe-NTA only developed multiple cysts composed of precancerous lesions with multilayered and proliferating large atypical cells. Mice treated with propolis and Artepillin C also had cysts, but these were dilated and composed of flat cells. These results suggest that propolis and Artepillin C prevent oxidative renal damage and the carcinogenesis induced by Fe-NTA in mice.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2000

Interleukin 18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn's disease.

BACKGROUND & AIMS: Crohn's disease (CD) is characterized by a marked accumulation of activated Th1 type CD4(+) T cells and macrophages in inflamed intestinal mucosa. Interleukin (IL)-18 is a recently described cytokine that mainly exists in activated macrophages and shares biological activities with IL-12 in driving the development of Th1 type CD4(+) T cells by inducing interferon gamma. To clarify the role of IL-18 in intestinal inflammation in CD, we assessed the functional role of IL-18 in regulating intestinal mucosal lymphocytes. METHODS: Serum IL-18 concentration was measured by enzyme-linked immunosorbent assay. Expression of IL-18 and IL-18 receptor in human intestinal mucosa was determined using immunohistochemistry and flow cytometry. The functional activity of IL-18 was assessed by the use of recombinant IL-18 to stimulate both the growth of intestinal mucosal lymphocytes and IL-2 receptor induction activity. RESULTS: The serum IL-18 concentration was significantly higher in patients with CD than normal controls. In the inflamed colonic mucosa of CD, many IL-18(+)CD68(+) macrophages had infiltrated the lamina propria. Intestinal mucosal lymphocytes from CD expressed functional IL-18 receptors. Recombinant IL-18 induced significant proliferative responses in freshly isolated mucosal lymphocytes from CD patients, but not from normal controls. IL-18 up-regulated IL-2 receptor expression in mucosal lymphocytes from patients with CD, but not from normal controls. CONCLUSIONS: These findings suggest that infiltrated macrophages in the inflamed intestinal mucosa in CD produce IL-18, and that macrophage-derived IL-18 may serve as a potent regulatory factor for intestinal mucosal lymphocytes, thereby contributing to chronic intestinal inflammation in CD.

Cell Division↗

PubMed2000

Clinical features in patients requiring reoperation after failed endoscopic procedures for hydrocephalus.

The aim of this study was to clarify the clinical features of patients at risk of secondary obstruction following endoscopic fenestration. Clinical notes and endoscopic findings for 15 patients treated with endoscopic procedures were retrospectively reviewed. Endoscopic third ventriculostomy (ETV) was performed as initial treatment in 4 patients with non-communicating hydrocephalus, including a neonate with myelomeningocele, and as an alternative to shunt revision in 4 patients. Two patients with non-communicating hydrocephalus caused by tumor or arachnoid cyst were also managed with third ventriculostomy. Four patients with loculated hydrocephalus underwent endoscopic septostomy. A child with an isolated fourth ventricle was treated with endoscopic aqueductoplasty. Of the 15 patients undergoing endoscopic procedure, 4 required reoperation. Of the 10 patients treated with ETV, only the neonate with myelomeningocele required a ventriculoperitoneal shunt because of failure of the initial procedure. Of the 4 patients treated with endoscopic septostomy, 2 children with loculated hydrocephalus following intraventricular hemorrhage (IVH) underwent a second septostomy. In a patient with an isolated fourth ventricle following posthemorrhagic hydrocephalus, recurrence was noted 8 months after the initial procedure. He underwent a second procedure using a stent implanted into the aqueduct to maintain CSF circulation. Sufficient stomal size or implantation of a stent may be required in the under-2-year age group with hydrocephalus accompanied by IVH and associated with myelomeningocele, in whom the risk of secondary obstruction may be high.

Adolescent↗

PubMed2000

Interleukin-18 in combination with IL-2 enhances natural killer cell activity without inducing large amounts of IFN-gamma in vivo.

Interleukin-18 (IL-18) is known to synergistically enhance murine natural killer (NK) cell activity in vitro when combined with either IL-12 or IL-2. However, it has also been demonstrated that simultaneous administration of IL-18 and IL-12 to mice induces extraordinarily large amounts of interferon-gamma (IFN-gamma) in the serum. In this study, we examined the effects of a combination of IL-18 and IL-2 on in vivo NK cell activation in parallel with the induction of toxicity. In contrast to the IL-18 and IL-12 combination, the combined administration of IL-18 and IL-2 to BALB/c mice for 3 days induced neither high levels of IFN-gamma production nor other visible side effects. When compared with treatment with IL-18 or IL-2 alone, the combined treatment resulted in a significant increase in the number of DX-5 (pan-NK cells marker)-positive cells in spleens and a marked enhancement of splenic NK activity, as determined by standard cytotoxicity assays. Enhanced splenic cytotoxicity generated in the mice treated with both IL-18 and IL-2 was also observed against syngeneic Colon 26 adenocarcinoma cells. Consistent with this in vitro observation, combined treatment produced a significantly stronger inhibitory effect on the pulmonary metastases following i.v. injection of Colon 26 tumor cells than treatment with either cytokine alone. These results suggest that IL-18 combined with IL-2 potentiates in vivo NK cell activity and contributes to inhibition of tumor metastasis without inducing significant toxicity.

Animals↗

PubMed2000

IL-12 synergizes with IL-18 or IL-1beta for IFN-gamma production from human T cells.

IL-18 is a proinflammatory cytokine that plays an important role in NK cell activation and T(h)1 response. IL-18 has a structural homology to IL-1, particularly IL-1beta. IL-18R, composed of IL-1R-related protein (IL-18Ralpha) and IL-1R accessory protein-like (IL-18Rbeta), belongs to the IL-1R family. Furthermore, IL-18R at least partly shares the signal transducing system with IL-1R. Thus, the IL-18-IL-18R system has a striking similarity to the IL-1-IL-1R system. For this reason, we regarded it important to investigate whether, like IL-18, IL-1beta synergizes with IL-12 in inducing IFN-gamma production from human T cells and plays an important role in the T(h)1 response. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R. Then, IL-12-stimulated T cells responded to IL-18 or IL-1beta by their proliferation and IFN-gamma production, although levels of IL-1beta-induced responses were lower. CD4(+)CD45RA(+) T cells, although they constitutively expressed IL-18Rbeta mRNA, did not express IL-18Ralpha mRNA. Phytohemagglutinin (PHA) stimulation alone induced IL-18Ralpha mRNA without affecting the expression of IL-18Rbeta mRNA. T(h)1-inducing conditions (PHA, IL-12 and anti-IL-4) further increased this expression. We also show that T(h)1 cells but not T(h)2 cells have increased expression of IL-18R and IL-1R, and produce IFN-gamma in response to IL-18 and/or IL-1beta.

Drug Synergism↗

PubMed2000

Sepsis after severe injury interrupts caspase-dependent processing of interleukin-18.

BACKGROUND: Cysteine proteases (caspases) participate in the activation process of interleukin-18 (IL-18), a key cytokine for septic organ failure. This study evaluates the influence of caspase blockade on secretion of IL-18 into whole blood in patients with multiple injuries and in patients with severe sepsis. METHODS: Heparinized blood was collected from patients with multiple injuries, from septic patients, as well as from healthy humans. Whole blood was stimulated for 24 hours with lipopolysaccharide (LPS) or Staphylococcus aureus in the presence or absence of the caspase inhibitors Z-VAD and Z-DEVD. IL-18 was measured by enzyme-linked immunosorbent assay. RESULTS: S. aureus Cowan strain differentially increased the release of IL-18 in the three study populations, whereas LPS was ineffective. Z-VAD and to a lesser degree Z-DEVD decreased (p < 0.05) S. aureus Cowan strain I-induced secretion of IL-18 into whole blood from control subjects and trauma patients. Caspase inhibitors did not influence release of IL-18 into whole blood from septic patients. CONCLUSION: Secretion of IL-18 into whole blood from healthy humans and trauma patients can be effectively controlled through blockade of caspase activity. In contrast, during sepsis, alternative mechanisms may regulate secretion of IL-18.

APACHE↗