Biomedical subjects

G Fantuzzi

Publications and source records attributed to G Fantuzzi.

At least 19 recordsLinked to original sources

PubMed2005

Defining the role of T cell-derived leptin in the modulation of hepatic or intestinal inflammation in mice.

The role of leptin in the immune system has been well established. While adipocytes represent the major source, leptin production by lymphocytes, infiltrating at the site of inflammation, was recently demonstrated. However, the significance of this locally released leptin remains unresolved. In the present study, two models in which absence of leptin-signalling is associated with protection were employed: the model of ConA-induced hepatitis and the CD4(+)CD45Rb(high) transfer model of colitis. For the ConA model, scid mice were reconstituted with either WT or leptin-deficient (ob/ob) CD4(+) T cells. Eight weeks post transfer, ConA was injected and serum ALT, TNFalpha, leptin as well as liver mononuclear cell activation and histological signs of inflammation were evaluated. No difference between recipients of WT or ob/ob cells was observed for any of the parameters evaluated. In the second model, either WT or ob/ob CD4(+)CD45Rb(high) cells were transferred into scid mice. No histological differences were detected, although recipients of ob/ob cells showed higher weight loss compared to recipients of WT cells. Spontaneous production of IL-6 from colon cultures obtained from recipients of ob/ob cells was reduced compared to recipients of WT cells, whereas stimulation of lamina propria lymphocytes with leptin resulted in a higher IFNgamma release in recipients of ob/ob cells compared to recipients of WT cells. In conclusion, the present study provides evidence that T cell-derived leptin does not play a major role in the regulation of the inflammatory process, indicating that the adipose tissue is the critical player in the immune-modulating effects of leptin.

Animals↗

PubMed2004

Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice.

BACKGROUND: Leptin regulates appetite through the long isoform of its receptor in the hypothalamus. Although leptin regulates immune responses, it is still unknown whether a direct effect of leptin on lymphocytes is required. AIMS: To clarify whether expression of leptin receptors on T lymphocytes modulates intestinal inflammation in mice. METHODS: The model of colitis induced by transfer of CD4(+)CD45RB(high) (RB(high)) cells into scid mice was used. Wild-type (WT) or leptin receptor deficient (db/db) RB(high) cells were transferred into scid mice and development of colitis evaluated. RESULTS: Leptin receptors were expressed on both RB(high) and RB(low) cells. Intestinal lymphocytes of mice with colitis expressed high leptin levels compared with healthy controls whereas the opposite was true for serum leptin levels. Transfer of RB(high) cells from db/db mice induced delayed disease compared with transfer of WT cells. A high rate of apoptosis in lamina propria lymphocytes and reduced cytokine production were observed early on in scid mice receiving db/db RB(high) cells. These effects were not due to the high levels of glucocorticoids present in db/db mice as administration of corticosterone to WT mice failed to reproduce this phenomenon. High expression of peroxisome proliferator activated receptor gamma was observed in the colon of recipients of db/db compared with WT cells. Freshly isolated db/db RB(high) cells produced low levels of interferon gamma. Despite delayed onset of colitis, as disease progressed differences between mice receiving WT or db/db cells were no longer apparent. CONCLUSIONS: These results suggest that leptin affects the immune response, partly by acting on the long isoform of its receptor expressed on T lymphocytes.

Animals↗

PubMed2002

Air quality and well-being perception in subjects attending university libraries in Modena (Italy).

We studied four libraries in the University of Modena and Reggio Emilia (Northern Italy) to determine the presence of polluting agents such as total dusts, formaldehyde and other volatile organic compounds (VOCs) including benzene, toluene and xylenes and to assess the sense of well-being perceived by library users. This investigation was suggested by an increase in reported symptoms related to Sick Building Syndrome (SBS) observed in recent decades among people spending most of their time in various indoor environments, including libraries. The microclimatic conditions and the concentrations of pollutants indicated an acceptable situation on the whole, even though a wide range of total dust values (40-350 microg/m3) and total VOCs (203-749 microg/m3) was observed. However, the perception of the different environmental parameters by the 130 library users that were interviewed identified the existence of some discomfort mainly caused by the feeling of poor ventilation. Moreover, 78.5% of the subjects stated they had at least one of the 16 investigated symptoms potentially related to a SBS. The place of occurrence of the self-reported symptoms was also investigated, the symptoms arising during library attendance more frequently than elsewhere were only four, and in particular feeling hot, sore eyes, dry throat and breathing difficulties. Overall, our study has shown the existence of an association between microclimatic perceptions as reported by library users and subjective symptoms related to SBS, considering the four libraries separately, the highest prevalence of self-reported symptoms was found in the library where environmental discomfort as perceived by users was greatest. Nevertheless, an association between subjective self-reported symptoms and both microclimatic conditions as resulted by instrumental measurements and/or pollutants concentrations was not apparent.

Adult↗

PubMed2001

IL-1 beta -converting enzyme (caspase-1) in intestinal inflammation.

IL-1 beta-converting enzyme (ICE; caspase-1) is the intracellular protease that cleaves the precursors of IL-1 beta and IL-18 into active cytokines. In the present study, the effect of ICE deficiency was evaluated during experimental colitis in mice. In acute dextran sulfate sodium-induced colitis, ICE-deficient (ICE KO) mice exhibited a greater than 50% decrease of the clinical scores weight loss, diarrhea, rectal bleeding, and colon length, whereas daily treatment with IL-1 receptor antagonist revealed a modest reduction in colitis severity. To further characterize the function of ICE and its role in intestinal inflammation, chronic colitis was induced over a 30-day time period. During this chronic time course, ICE KO mice exhibited a near complete protection, as reflected by significantly reduced clinical scores and almost absent histological signs of colitis. Consistently, colon shortening occurred only in dextran sulfate sodium-exposed wild-type mice but not in ICE KO mice. Protection was accompanied by reduced spontaneous release of the proinflammatory cytokines IL-18, IL-1 beta, and IFN-gamma from total colon cultures. In addition, flow cytometric analysis of isolated mesenteric lymph node cells revealed evidence of reduced cell activation in ICE KO mice as evaluated by surface expression of CD3 CD69 and CD4 CD25. We conclude that inhibition of ICE represents a novel anti-inflammatory strategy for intestinal inflammation.

Animals↗

PubMed2001

A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18.

IL-18 binding protein (IL-18BP) is a circulating antagonist of the proinflammatory Th1 cytokine IL-18. It effectively blocks IL-18 by forming a 1:1 high affinity (Kd=400 pM) complex, exhibiting a very low dissociation rate. We have developed a sandwich ELISA for IL-18BPa and determined its limit of detection (62 pg/ml). Interference by IL-18 and related cytokines, as well as cross reactivity with other IL-18BP isoforms (b, c, and d) were determined. Using this ELISA, we measured serum IL-18BPa in large cohorts of healthy individuals and in septic patients. Serum IL-18BPa in healthy individuals was 2.15+/-0.15 ng/ml (range 0.5-7 ng/ml). In sepsis, the level rose to 21.9+/-1.44 ng/ml (range 4-132 ng/ml). Total IL-18 was measured in the same sera by an electrochemiluminescence assay and free IL-18 was calculated based on the mass action law. Total IL-18 was low in healthy individuals (64+/-17 pg/ml) and most of it ( approximately 85%) was in its free form. Total IL-18 and IL-18BPa were both elevated in sepsis patients upon admission (1.5+/-0.4 ng/ml and 28.6+/-4.5 ng/ml, respectively). At these levels, most of the IL-18 is bound to IL-18BPa, however the remaining free IL-18 is still higher than in healthy individuals. We conclude that IL-18BPa considerably inhibits circulating IL-18 in sepsis. Yet, exogenous administration of IL-18BPa may further reduce circulating IL-18 activity.

Alternative Splicing↗

PubMed2001

Regulation of free and bound leptin and soluble leptin receptors during inflammation in mice.

Leptin, an appetite-regulating hormone/cytokine, circulates both free and bound to soluble leptin receptors (s-leptin R). An electrochemiluminescence (ECL) assay for the quantitative measurement of murine s-leptin R was developed. The absence of s-leptin R immunoreactivity in the serum of db(pas)/db(pas)mice demonstrated the specificity of the assay, which detected s-leptin R both in the free form and complexed with leptin. The distribution of free vs bound leptin and the regulation of s-leptin R were evaluated in mice following administration of the pro-inflammatory stimuli endotoxin (100 microg/mouse) and turpentine (100 microl/mouse). Both endotoxin and turpentine significantly increased serum leptin and s-leptin R levels compared to control mice. The distribution of free vs bound leptin was not altered by administration of endotoxin or turpentine. In fact, approximately 50% of total leptin was present in the free form in either control, endotoxin- or turpentine-injected mice. On the contrary, during the hyperleptinemia of pregnancy, only 10% of total leptin was present in the free form. We conclude that inflammation leads to the increase of both bound and free leptin. Therefore, the total amount of bioactive leptin is increased during acute inflammation, suggesting that leptin participates in the host response to inflammation.

Animals↗

PubMed2001

Defective localization of the NADPH phagocyte oxidase to Salmonella-containing phagosomes in tumor necrosis factor p55 receptor-deficient macrophages.

Tumor necrosis factor receptor (TNFR) p55-knockout (KO) mice are susceptible profoundly to Salmonella infection. One day after peritoneal inoculation, TNFR-KO mice harbor 1,000-fold more bacteria in liver and spleen than wild-type mice despite the formation of well organized granulomas. Macrophages from TNFR-KO mice produce abundant quantities of reactive oxygen and nitrogen species in response to Salmonella but nevertheless exhibit poor bactericidal activity. Treatment with IFN-gamma enhances killing by wild-type macrophages but does not restore the killing defect of TNFR-KO cells. Bactericidal activity of macrophages can be abrogated by a deletion in the gene encoding TNFalpha but not by saturating concentrations of TNF-soluble receptor, suggesting that intracellular TNFalpha can regulate killing of Salmonella by macrophages. Peritoneal macrophages from TNFR-KO mice fail to localize NADPH oxidase-containing vesicles to Salmonella-containing vacuoles. A TNFR-KO mutation substantially restores virulence to an attenuated mutant bacterial strain lacking the type III secretory system encoded by Salmonella pathogenicity island 2 (SPI2), suggesting that TNFalpha and SPI2 have opposing actions on a common pathway of vesicular trafficking. TNFalpha-TNFRp55 signaling plays a critical role in the immediate innate immune response to an intracellular pathogen by optimizing the delivery of toxic reactive oxygen species to the phagosome.

Animals↗

PubMed2001

Occupational exposure to trihalomethanes in indoor swimming pools.

The study evaluated occupational exposure to trihalomethanes (THMs) in indoor swimming pools. Thirty-two subjects, representing the whole workforce employed in the five public indoor swimming pools in the city of Modena (Northern Italy) were enrolled. Both environmental and biological monitoring of THMs exposure were performed. Environmental concentrations of THMs in different areas inside the swimming pools (at the poolside, in the reception area and in the engine-room) were measured as external exposure index, while individual exposure of swimming pool employees was estimated by THMs concentration in alveolar air. The levels of THMs observed in swimming pool water ranged from 17.8 to 70.8 microg/l; the mean levels of THMs in ambient air were 25.6+/-24.5 microg/m3 in the engine room, 26.1+/-24.3 microg/m3 in the reception area and 58.0+/-22.1 microg/m3 at the poolside. Among THMs, only chloroform and bromodichloromethane were always measured in ambient air, while dibromochloromethane was detected in ambient air rarely and bromoform only once. Biological monitoring results showed a THMs mean value of 20.9+/-15.6 microg/m3. Statistically significant differences were observed according to the main job activity: in pool attendants, THMs alveolar air were approximately double those observed in employees working in other areas of the swimming pools (25.1+/-16.5 microg/m3 vs. 14.8+/-12.3 microg/m3, P < 0.01). THMs in alveolar air samples were significantly correlated with THMs concentrations in ambient air (r = 0.57; P < 0.001). Indoor swimming pool employees are exposed to THMs at ambient air levels higher than the general population. The different environmental exposure inside the swimming pool can induce a different internal dose in exposed workers. The correlation found between ambient and alveolar air samples confirms that breath analysis is a good biological index of occupational exposure to these substances at low environmental levels.

Adult↗

PubMed2001

Functional reconstitution and regulation of IL-18 activity by the IL-18R beta chain.

IL-18 and IL-12 are major IFN-gamma-inducing cytokines but the unique synergism of IL-18 and IL-12 remains unclear. In the human NK cell line NKO, IL-18R alpha, and IL-18R beta are expressed constitutively but IL-18 did not induce IFN-gamma unless IL-12 was present. COS-1 fibroblasts, which produce the chemokine IL-8 when stimulated by IL-1 beta or TNF-alpha, do not respond to IL-18, despite abundant expression of the IL-18R alpha chain. COS-1 cells lack expression of the IL-18R beta chain. The IL-18R beta cDNA was cloned from a human T-B lymphoblast cDNA library and COS-1 cells were transiently transfected with the IL-18R beta chain and a luciferase reporter. In transfected COS-1 cells, IL-18 induced IL-8 and luciferase in the absence of IL-12 and independently of IL-1 and TNF. Ab against the IL-18R alpha chain, however, prevented IL-18 responsiveness in COS-1 cells transfected with the IL-18R beta chain, suggesting that both chains be functional. In NKO cells and PBMC, IL-12 increased steady-state mRNA levels of IL-18R alpha and IL-18R beta; the production of IFN-gamma corresponded to IL-12-induced IL-18R alpha and IL-18R beta chains. We conclude that functional reconstitution of the IL-18R beta chain is essential for IL-12-independent proinflammatory activity of IL-18-induced IL-8 in fibroblasts. The synergism of IL-18 plus IL-12 for IFN-gamma production is, in part, due to IL-12 up-regulation of both IL-18R alpha and IL-18R beta chains, although postreceptor events likely contribute to IFN-gamma production.

Animals↗

PubMed2001

Role of interferon regulatory factor-1 in the regulation of IL-18 production and activity.

Interferon regulatory factor-1 (IRF-1) is a transcription factor regulating the expression of several cytokines. Using IRF-1 knockout (KO) mice, the role of IRF-1 in the production and activity of IL-18 was evaluated. Administration of IL-12 or concanavalin A significantly increased levels of circulating IL-18 in wild-type (WT), but not in IRF-1 KO mice. However, despite these differences in circulating IL-18 levels, no or only minor differences in constitutive or inducible IL-18 mRNA and tissue-associated protein levels were observed between WT and IRF-1 KO mice. On the other hand, we observed that constitutive and inducible levels of the IL-18-processing enzyme caspase-1 were markedly reduced in the spleen and the liver of IRF-1 KO compared to WT mice. In addition, both constitutive and inducible liver mRNA levels for the IL-18 binding protein (IL-18BP), a specific IL-18 antagonist, were significantly lower in IRF-1 KO than in WT mice. Compared to IL-12, IL-18 only weakly induced IRF-1 mRNA in cultured splenocytes. However, IL-18-induced IFN-gamma production was strongly reduced in splenocytes from IRF-1 KO compared to WT cells. In conclusion, IRF-1 regulates IL-18 production and activity mostly by modulating expression of caspase-1 and IL-18BP. In addition, IRF-1 participates in the induction of IFN-gamma by IL-18.

Animals↗

PubMed2001

Production of IL-1 receptor antagonist by hepatocytes is regulated as an acute-phase protein in vivo.

IL-1 receptor antagonist (IL-1Ra) is produced by isolated human hepatocytes with characteristics of an acute-phase protein. There are multiple IL-1Ra peptides, one secreted (sIL-1Ra) and three intracellular (icIL-1Ra1, 2, 3). sIL-1Ra, but not icIL-1Ra1, mRNA is transcribed by cultured human hepatocytes. In this study, we examined in vivo production of IL-1Ra by the liver in mice in two experimental models of acute-phase response, systemic lipopolysaccharide (LPS) administration and local turpentine injection. Liver sIL-1Ra expression was up-regulated in response to both types of stimulation. After LPS injection, the hepatic production of sIL-1Ra correlated with the increase in plasma IL-1Ra levels. In addition, the total amount of IL-1Ra present in the liver after LPS injection was six- and tenfold higher than in the lung and spleen. As assessed by in situ hybridization, sIL-1Ra, but not icIL-1Ra, mRNA was produced by hepatocytes in vivo after LPS injection. Using IL-6(-/-) mice, we demonstrated that in turpentine-induced inflammation production of IL-1Ra mRNA by the liver is regulated by IL-6. In contrast, local production of IL-1Ra is independent of IL-6. Taken together, these results indicate that IL-1Ra is produced by the liver as an acute-phase protein in vivo.

Acute-Phase Proteins↗

PubMed2001

Lessons from interleukin-deficient mice: the interleukin-1 system.

The study of cytokine-deficient mice has provided important information for a better understanding of inflammatory processes. In this report, the characterization of mice deficient for various components of the interleukin (IL)-1 system is reviewed. Results obtained by studying mice deficient for IL-1alpha, IL-1beta, IL-1 receptor antagonist, IL-1 receptor type I, IL-1 receptor accessory protein, IL-1 receptor-associated kinase, and the IL-1beta-converting enzyme caspase-1 are summarized. Because some of the components of the IL-1 system are shared with IL-18, similarities between IL-1beta and IL-18 are also discussed.

Animals↗

PubMed2001

Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production.

Interleukin (IL)-18, initially described as interferon (IFN)-gamma-inducing factor, is expressed in the inflamed mucosa of patients with Crohn's disease. To investigate the role of IL-18 in intestinal inflammation, the effect of neutralizing antimurine IL-18 antiserum in dextran sulfate sodium (DSS)-induced colitis in BALB/c and C57BL/6 mice was examined. During a dose response of DSS, levels of colonic IL-18 increased parallel with clinical worsening. With the use of confocal laser microscopy, the increased IL-18 was localized to the intestinal epithelial layer. Anti-IL-18 treatment resulted in a dose-dependent reduction of the severity of colitis in both BALB/c and C57BL/6 mice. Colon shortening following DSS-induced colitis was partially prevented in the treatment groups. In the colon tissue homogenates, IFN-gamma concentrations were lower in the anti-IL-18-treated DSS-fed mice compared with untreated DSS-fed mice. This suppressive effect of anti-IL-18 administered in vivo was also observed on spontaneous tumor necrosis factor-alpha, IL-18, and IFN-gamma production from ex vivo colon organ cultures. The stimulation of lamina propria mononuclear cells by IL-18 and IL-12 resulted in a synergistic increase in IFN-gamma synthesis. These findings suggest that IL-18 is a pivotal mediator in experimental colitis.

Animals↗

PubMed2001

Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure.

We sought to determine whether mice deficient in the proinflammatory caspase-1, which cleaves precursors of IL-1 beta and IL-18, were protected against ischemic acute renal failure (ARF). Caspase-1(-/-) mice developed less ischemic ARF as judged by renal function and renal histology. These animals had significantly reduced blood urea nitrogen and serum creatinine levels and a lower morphological tubular necrosis score than did wild-type mice with ischemic ARF. Since caspase-1 activates IL-18, lack of mature IL-18 might protect these caspase-1(-/-) mice from ARF. In wild-type animals, we found that ARF causes kidney IL-18 levels to more than double and induces the conversion of the IL-18 precursor to the mature form. This conversion is not observed in caspase-1(-/-) ARF mice or sham-operated controls. We then injected wild-type mice with IL-18-neutralizing antiserum before the ischemic insult and found a similar degree of protection from ARF as seen in caspase-1(-/-) mice. In addition, we observed a fivefold increase in myeloperoxidase activity in control mice with ARF, but no such increase in caspase-1(-/-) or IL-18 antiserum-treated mice. Finally, we confirmed histologically that caspase-1(-/-) mice show decreased neutrophil infiltration, indicating that the deleterious role of IL-18 in ischemic ARF may be due to increased neutrophil infiltration.

Acute Kidney Injury↗

PubMed2000

Prevalence of urinary incontinence among institutionalized patients: a cross-sectional epidemiologic study in a midsized city in northern Italy.

OBJECTIVES: To determine the prevalence of urinary incontinence among institutionalized elderly people. METHODS: A cross-sectional study was conducted on 839 subjects, resident in 14 residential or nursing homes. A questionnaire was administered to the study population and their clinical records were reviewed. RESULTS: The overall prevalence of urinary incontinence was 54.5%, higher in women (59.8%) than in men (39.2%). The prevalence increased significantly with age, from 26.5% in subjects 65 years old or younger to 73.7% in subjects 95 years old or older; with worsening of mental status, from 36.2% in well-oriented subjects to 76.7% in poorly oriented subjects; and with worsening of mobility, from 23.8% in self-sufficient subjects to 82.1% in bedridden patients. The prevalence was significantly associated with parity, from 54.1% in nulliparous women to 65.4% in multiparous women. Urinary incontinence was also associated with urinary tract infection, constipation, and fecal incontinence. CONCLUSIONS: The results of our study are in accordance with other similar studies. That more than one half of the elderly residents of nursing and residential homes have urinary incontinence shows the relevance of this condition. We believe that urinary incontinence in institutionalized elderly people can be managed essentially by measures of tertiary prevention, aimed at reducing the handicapping conditions and at slowing down the process of self-sufficiency impairment.

Adult↗

PubMed2000

Neutralization of IL-18 reduces neutrophil tissue accumulation and protects mice against lethal Escherichia coli and Salmonella typhimurium endotoxemia.

In addition to stimulating IFN-gamma synthesis, IL-18 also possesses inflammatory effects by inducing synthesis of the proinflammatory cytokines TNF and IL-1beta and the chemokines IL-8 and macrophage inflammatory protein-1alpha. We hypothesized that neutralization of IL-18 would have a beneficial effect in lethal endotoxemia in mice. IL-1beta converting enzyme (ICE)-deficient mice, lacking the ability to process mature IL-18 and IL-1beta, were completely resistant to lethal endotoxemia induced by LPS derived from either Escherichia coli or Salmonella typhimurium. In contrast, both wild-type and IL-1beta-/- mice were equally susceptible to the lethal effects of LPS, implicating that absence of mature IL-18 or IFN-gamma but not IL-1beta in ICE-/- mice is responsible for this resistance. However, IFN-gamma-deficient mice were not resistant to S. typhimurium LPS, suggesting an IFN-gamma-independent role for IL-18. Anti-IL-18 Abs protected mice against a lethal injection of either LPS. Anti-IL-18 treatment also reduced neutrophil accumulation in liver and lungs. The increased survival was accompanied by decreased levels of IFN-gamma and macrophage inflammatory protein-2 in anti-IL-18-treated animals challenged with E. coli LPS, whereas IFN-gamma and TNF concentrations were decreased in treated mice challenged with S. typhimurium. In conclusion, neutralization of IL-18 during lethal endotoxemia protects mice against lethal effects of LPS. This protection is partly mediated through inhibition of IFN-gamma production, but mechanisms involving decreased neutrophil-mediated tissue damage due to the reduction of either chemokines (E. coli LPS) or TNF (S. typhimurium LPS) synthesis by anti-IL-18 treatment may also be involved.

Animals↗

PubMed2000

Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor alpha and IL-18.

The role of leptin was investigated in two models of T cell-mediated hepatitis: the administration of Con A or of Pseudomonas aeruginosa exotoxin A (PEA). In both models, leptin-deficient (ob/ob) mice were protected from liver damage and showed lower induction of tumor necrosis factor (TNF) alpha and IL-18 compared with their lean littermates. Neutralization of TNF-alpha reduced induction of IL-18 by either Con A (70% reduction) or PEA (40% reduction). Pretreatment of lean mice with either soluble TNF receptors or with an anti-IL-18 antiserum significantly reduced Con A- and PEA-induced liver damage. The simultaneous neutralization of TNF-alpha and IL-18 fully protected the mice against liver toxicity. However, neutralization of either IL-18 or TNF-alpha did not inhibit Con A-induced production of IFN-gamma. Thymus atrophy and alterations in the number of circulating lymphocytes and monocytes were observed in ob/ob mice. Exogenous leptin replacement restored the responsiveness of ob/ob mice to Con A and normalized their lymphocyte and monocyte populations. These results demonstrate that leptin deficiency leads to reduced production of TNF-alpha and IL-18 associated with reduced T cell-mediated hepatotoxicity. In addition, both TNF-alpha and IL-18 appear to be essential mediators of T cell-mediated liver injury.

ADP Ribose Transferases↗

PubMed2000

IL-18 binding protein increases spontaneous and IL-1-induced prostaglandin production via inhibition of IFN-gamma.

IL-18 shares with IL-1 the same family of receptors and several identical signal transduction pathways. Because of these similarities, IL-18 was investigated for its ability to induce prostaglandin E(2) (PGE(2)) synthesis in human peripheral blood mononuclear cells (PBMC), a prominent, proinflammatory property of IL-1. IL-18 was highly active in PBMC by inducing the synthesis of the chemokine IL-8; however, no induction of PGE(2) synthesis nor cyclooxygenase type-2 gene expression was observed in PBMC stimulated with IL-18. In the same cultures, IL-1beta induced a 12-fold increase in PGE(2). Although IL-1beta-induced IL-8 synthesis was augmented 3-fold by IL-18, IL-18 suppressed IL-1beta-induced PGE(2) production by 40%. The suppressive effect of IL-18 on PGE(2) production was mediated by interferon (IFN)-gamma because anti-human IFN-gamma-antibody prevented IL-18-induced reduction in PGE(2). Consistent with these observations, IL-12, a known inducer of IFN-gamma, augmented IL-1beta-induced IFN-gamma but suppressed IL-1beta-induced PGE(2) by 75%. IL-18 binding protein (IL-18BP) is a naturally occurring and specific inhibitor of IL-18. When recombinant IL-18BP was added to PBMC cultures, unexpectedly, spontaneous PGE(2) production increased. PGE(2) production was also increased by the addition of IL-18BP to PBMC stimulated with either IL-1beta or IL-12 and also in whole blood cultures stimulated with Staphylococcus epidermidis. These studies demonstrate that IL-18BP decreases endogenous IL-18 activity by reducing IFN-gamma-mediated responses.

Cells, Cultured↗