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Showing papers by "Charles A. Dinarello published in 2003"


Journal ArticleDOI
TL;DR: The anti-angiogenic effects of IL-1 receptor antagonist, shown here, suggest a possible therapeutic role in cancer, in addition to its current use in rheumatoid arthritis.
Abstract: Here, we describe that microenvironmental IL-1β and, to a lesser extent, IL-1α are required for in vivo angiogenesis and invasiveness of different tumor cells. In IL-1β knockout (KO) mice, local tumor or lung metastases of B16 melanoma cells were not observed compared with WT mice. Angiogenesis was assessed by the recruitment of blood vessel networks into Matrigel plugs containing B16 melanoma cells; vascularization of the plugs was present in WT mice, but was absent in IL-1β KO mice. The addition of exogenous IL-1 into B16-containing Matrigel plugs in IL-1β KO mice partially restored the angiogenic response. Moreover, the incorporation of IL-1 receptor antagonist to B16-containing plugs in WT mice inhibited the ingrowth of blood vessel networks into Matrigel plugs. In IL-1α KO mice, local tumor development and induction of an angiogenic response in Matrigel plugs was less pronounced than in WT mice, but significantly higher than in IL-1β KO mice. These effects of host-derived IL-1α and IL-1β were not restricted to the melanoma model, but were also observed in DA/3 mammary and prostate cancer cell models. In addition to the in vivo findings, IL-1 contributed to the production of vascular endothelial cell growth factor and tumor necrosis factor in cocultures of peritoneal macrophages and tumor cells. Host-derived IL-1 seems to control tumor angiogenesis and invasiveness. Furthermore, the anti-angiogenic effects of IL-1 receptor antagonist, shown here, suggest a possible therapeutic role in cancer, in addition to its current use in rheumatoid arthritis.

953 citations


Journal ArticleDOI
TL;DR: In this paper, the authors support a key role for cytokines in left ventricular remodeling in congestive heart failure (CHF) patients and show that elevated plasma cytokine levels are associated with increased mortality.
Abstract: Background— Experimental studies support a key role for cytokines in left ventricular remodeling. In congestive heart failure (CHF) patients, elevated plasma cytokine levels are associated with wor...

687 citations


Journal ArticleDOI
TL;DR: Greater levels or production of the catabolic cytokines TNF-alpha and interleukin 6 are associated with increased mortality in community-dwelling elderly adults, whereas IGF-1 levels had the opposite effect.

383 citations


Journal ArticleDOI
TL;DR: Interferon (IFN)-gamma-inducing factor appears to be a viable clinical target to combat the pathologic consequences of sepsis via IFN-gamma mechanisms.
Abstract: Interferon (IFN)-gamma-inducing factor was previously termed interleukin (IL)-18. Although IL-12 is also an IFN-gamma-inducing factor, the activity of IL-18 (but not IL-12) in models of sepsis and death is dependent on the intracellular cysteine protease IL-1beta converting enzyme (caspase-1). Caspase-1 is required for cleavage of the inactive precursor form of IL-18 into an active cytokine, and caspase-1-deficient mice are resistant to lethal endotoxemia. The absence of IFN-gamma (but not IL-1beta) in caspase-1-deficient mice is responsible for this resistance. However, the role of IFN-gamma in murine defense against gram-negative infection is inconsistent. Mice deficient in IFN-gamma are not resistant to lethal endotoxemia but are resistant when treated with neutralizing antibodies to IL-18 and challenged with a lethal injection of some endotoxins. Anti-IL-18 treatment also reduces neutrophil accumulation in liver and lungs. Neutralizing IL-18 with the IL-18 binding protein protects mice against endotoxin- and ischemia-induced hepatic damage. Thus, blockade of IL-18 appears to be a viable clinical target to combat the pathologic consequences of sepsis via IFN-gamma mechanisms.

279 citations


Journal ArticleDOI
TL;DR: Plasma proinflammatory cytokine profiles in patients with sepsis due to gram-positive and gram-negative bacteria are investigated and the cytokine production and differential gene regulation of leukocytes stimulated ex vivo with Escherichia coli lipopolysaccharide or heat-killed Staphylococcus aureus is studied.
Abstract: Sepsis caused by gram-negative bacteria and that caused by gram-positive bacteria often manifest similar clinical features. We investigated plasma proinflammatory cytokine profiles in patients with sepsis due to gram-positive and gram-negative bacteria and studied the cytokine production and differential gene regulation of leukocytes stimulated ex vivo with Escherichia coli lipopolysaccharide or heat-killed Staphylococcus aureus. Concentrations of tumor necrosis factor alpha, interleukin 1 receptor antagonist (IL-1Ra), IL-8, IL-10, IL-18 binding protein, procalcitonin, and protein C in plasma did not differ between patients with sepsis due to gram-negative and gram-positive bacteria. However, plasma IL-1, IL-6, and IL-18 concentrations were significantly higher in patients with sepsis due to gram-positive bacteria. Ex vivo stimulation of whole blood with heat-killed S. aureus markedly increased IL-1 and IL-18 levels more than E. coli lipopolysaccharide stimulation. Microarray analysis revealed at least 359 cross-validated probe sets (genes) significant at the P < 0.001 level whose expression discriminated among gram-negative-organism-stimulated, gram-positive-organism-stimulated, and unstimulated whole-blood leukocytes. The host inflammatory responses to gramnegative and gram-positive stimuli share some common response elements but also exhibit distinct patterns of cytokine appearance and leukocyte gene expression. Despite improvements in hemodynamic monitoring, antibiotics, and other supportive therapies, sepsis remains the most common cause of death within intensive care units (27) and the 13th leading cause of death overall in the United States (10). More than 500,000 people are diagnosed with sepsis each year in the United States, and the observed incidence is still rising (3, 26, 35), with financial costs exceeding $16 billion each year (3).

223 citations


Journal ArticleDOI
TL;DR: The prognostic role of the inflammatory cytokine, interleukin 6 (IL‐6), and insulin‐like growth factor‐1 (IGF‐1) in predicting 2‐year changes in fat‐free mass (FFM) while controlling for potential confounders is assessed.
Abstract: Objectives: To assess the prognostic role of the inflammatory cytokine, interleukin 6 (IL-6), and insulin-like growth factor-1 (IGF-1) in predicting 2-year changes in fat-free mass (FFM) while controlling for potential confounders. Design: Population-based cohort, the Framingham Heart Study, examined in 1992–93 and 1994–95. Setting: General community. Participants: Two hundred thirty-two men and 326 women aged 72 to 92. Measurements: IGF-1 was measured using radio-immunoassay and cellular IL-6 production using non-cross-reacting radioimmunoassays. FFM was estimated using population-specific equations for predicting FFM from bioelectrical impedance analysis developed separately for men and women. Results: Higher IGF-1 predicted smaller loss of FFM in men than lower IGF-1 did (P=.002), after adjusting for age, baseline FFM, fat mass, and 2-year weight changes, whereas cellular IL-6 was a significant predictor of sarcopenia in women (P=.02). Weight change was a strong determinant of change in FFM in both sexes (P<.0001). Conclusion: Predictors of sarcopenia include body composition characteristics that are common to men and women and sex-specific metabolic predictors. Sarcopenia appears to reflect a withdrawal of anabolic stimuli, such as growth hormone, in men but an increase in catabolic stimuli, such as cellular IL-6, in women.

212 citations


Journal ArticleDOI
TL;DR: IL-1α reduces tumorigenicity by inducing antitumor immunity, whereas IL-1β promotes invasiveness, including tumor angiogenesis, and also induces immune suppression in the host, this is, to the authors' knowledge, the first report on differential, nonredundant, in vivo effects of IL- 1α and IL-2β in malignant processes.
Abstract: In this study, we show that distinct compartmentalization patterns of the IL-1 molecules (IL-1alpha and IL-1beta), in the milieu of tumor cells that produce them, differentially affect the malignant process. Active forms of IL-1, namely precursor IL-1alpha (pIL-1alpha), mature IL-1beta (mIL-1beta), and mIL-1beta fused to a signal sequence (ssIL-1beta), were transfected into an established fibrosarcoma cell line, and tumorigenicity and antitumor immunity were assessed. Cell lines transfected with pIL-1alpha, which expresses IL-1alpha on the membrane, fail to develop local tumors and activate antitumor effector mechanisms, such as CTLs, NK cells, and high levels of IFN-gamma production. Cells transfected with secretable IL-1beta (mIL-1beta and ssIL-1beta) were more aggressive than wild-type and mock-transfected tumor cells; ssIL-1beta transfectants even exhibited metastatic tumors in the lungs of mice after i.v. inoculation (experimental metastasis). In IL-1beta tumors, increased vascularity patterns were observed. No detectable antitumor effector mechanisms were observed in spleens of mice injected with IL-1beta transfectants, mock-transfected or wild-type fibrosarcoma cells. Moreover, in spleens of mice injected with IL-1beta transfectants, suppression of polyclonal mitogenic responses (proliferation, IFN-gamma and IL-2 production) to Con A was observed, suggesting the development of general anergy. Histologically, infiltrating mononuclear cells penetrating the tumor were seen at pIL-1alpha tumor sites, whereas in mIL-1beta and ssIL-1beta tumor sites such infiltrating cells do not penetrate inside the tumor. This is, to our knowledge, the first report on differential, nonredundant, in vivo effects of IL-1alpha and IL-1beta in malignant processes; IL-1alpha reduces tumorigenicity by inducing antitumor immunity, whereas IL-1beta promotes invasiveness, including tumor angiogenesis, and also induces immune suppression in the host.

145 citations


Journal ArticleDOI
01 Jun 2003-Vaccine
TL;DR: There is a growing body of clinical evidence that neutralization of TNF-alpha is associated with an increased risk of opportunistic infections, including mycobacterial diseases, and blockade of IL-1 activity with the IL- 1 receptor antagonist (IL-1Ra) appears, at present, to be relatively safe.

142 citations


Journal ArticleDOI
TL;DR: The mechanisms of mIL-18BP inhibition of CIA include reductions in cell-mediated and humoral immunity to collagen as well as decreases in production of proinflammatory cytokines in the spleen and joints.
Abstract: IL-18 is an important cytokine in autoimmune and inflammatory diseases through the induction of IFN-gamma, TNF-alpha, and IL-1 We report herein that collagen-induced arthritis (CIA) in mice is inhibited by treatment with murine IL-18 binding protein (mIL-18BP) CIA was induced in DBA/1J mice by the injection of bovine type II collagen (CII) in IFA with added Mycobacterium tuberculosis on days 0 and 21 The mice were then treated for 3 wk with PBS or with two doses of mIL-18BP (05 and 3 mg/kg) as a fusion protein with the Fc portion of murine IgG1 Both the clinical disease activity scores and the histological scores of joint damage were reduced 50% in mice treated with either dose of mIL-18BP Proliferation of CII-stimulated spleen and lymph node cells as well as the change in serum levels of IgG1 and IgG2a Ab to collagen between days 21 and 42 were decreased in mice treated with mIL-18BP The production of IFN-gamma, TNF-alpha, and IL-1beta in cultured spleen cells was reduced by in vivo treatment with low dose, but not high dose, mIL-18BP FACS analysis showed a slight decrease in NK cells and an increase in CD4(+) T cells in spleens of mice treated with mIL-18BP The steady state mRNA levels of IFN-gamma, TNF-alpha, and IL-1beta in isolated joints were all decreased in mice treated with both doses of mIL-18BP The mechanisms of mIL-18BP inhibition of CIA include reductions in cell-mediated and humoral immunity to collagen as well as decreases in production of proinflammatory cytokines in the spleen and joints

141 citations


Journal ArticleDOI
TL;DR: The concept that IL-18 plays a major role in the pathogenesis of the autoimmune syndrome of lpr mice and that a reduction inIL-18 activity could be a therapeutic strategy in autoimmune diseases is supported.
Abstract: The lupus-like autoimmune syndrome of MRL/Mp-Tnfrsf6lpr (lpr) mice is characterized by progressive lymphadenopathy and autoantibody production, leading to early death from renal failure. Activation of T helper lymphocytes is one of the events in the pathogenesis of the disease in these mice and likely in human systemic lupus erythematosus. Among T helper lymphocytedependent cytokines, IFN-γ plays a pivotal role in the abnormal cell activation and the fatal development of the lpr disease. IL-18, an inducer of IFN-γ in T lymphocytes and natural killer cells, may contribute to the disease because cells from lpr mice are hypersensitive to IL-18 and express high levels of IL-18. To assess the contribution of IL-18 to the pathogenesis in the animal model, in vivo inhibition of IL-18 was attempted. Young lpr mice were vaccinated against autologous IL-18 by repeated administration of a cDNA coding for the murine IL-18 precursor. Vaccinated mice produced autoantibodies to murine IL-18 and exhibited a significant reduction in spontaneous lymphoproliferation and IFN-γ production as well as less glomerulonephritis and renal damage. Moreover, mortality was significantly delayed in anti-IL-18-vaccinated mice. These studies support the concept that IL-18 plays a major role in the pathogenesis of the autoimmune syndrome of lpr mice and that a reduction in IL-18 activity could be a therapeutic strategy in autoimmune diseases.

128 citations


Journal Article
TL;DR: A significant role is demonstrated on hepatic metastasis by up-regulating melanoma cell adhesion to HSE cells and tumor growth, implicating a possible antimetastatic benefit of neutralizing IL-18.
Abstract: We studied the role of endogenous interleukin (IL)-18 in hepatic metastasis by blocking this cytokine using the naturally occurring IL-18 binding protein (IL-18BP). A single i.p. dose of IL-18BP given 30 min before intrasplenic injection of murine B16 melanoma (B16M) cells reduced the number of hepatic metastatic foci by 75% and metastatic volume by 80%. Same treatment reduced the intrahepatic retention of luciferase-transfected B16M by 50% and abolished VCAM-1 up-regulation in the hepatic microvasculature, as assessed by reverse transcription-PCR, Western blot, and immunohistochemistry. Twelve hours after IL-18BP, hepatic sinusoidal endothelium (HSE) cells were isolated, and adhesion of B16M cells to these cultured HSE cells was reduced to the level of vehicle-treated mice. IL-18BP treatment of mice with established micrometastases resulted in a 25% decrease in metastasis number and 40% decrease in metastasis volume, suggesting inhibition of endogenous growth factors. Indeed, the addition of IL-18BP to normal HSE abolished the release of melanoma cell growth factor(s) induced by B16M. IL-18 promoted the in vitro growth of B16M and human melanoma cells, which was IL-1 dependent. These data demonstrate a significant role of endogenous IL-18 on hepatic metastasis by up-regulating melanoma cell adhesion to HSE cells and tumor growth, implicating a possible antimetastatic benefit of neutralizing IL-18.

Journal ArticleDOI
TL;DR: It is suggested that E. histolytica may block the host inflammatory response by a novel mechanism, inactivation of IL-18, which results from a complex interplay of parasite virulence factors and host defenses.
Abstract: Amebiasis is a major cause of morbidity and mortality worldwide. Invasion by Entamoeba histolytica trophozoites causes secretion of proinflammatory cytokines from host epithelial cells, leading to a local acute inflammatory response, followed by lysis of colonic cells. Extracellular cysteine proteinases from amebic trophozoites are key virulence factors and have a number of important interactions with host defenses, including cleavage of immunoglobulin G (IgG), IgA, and complement components C3 and C5. Amebic lysates have also been shown to activate the precursor to interleukin 1-beta (proIL-1beta), mimicking the action of caspase-1. IL-18 is also a central cytokine, which induces gamma interferon (IFN-gamma) and activates macrophages, one of the main host defenses against invading trophozoites. Because proIL-18 is also activated by caspase-1, we evaluated whether amebic proteinases had a similar effect. Instead, we found that recombinant proIL-18 was cleaved into smaller fragments by the complex of surface-associated and released amebic proteinases. To evaluate the function of an individual proteinase from the complex pool, we expressed an active surface proteinase, EhCP5, which is functional only in E. histolytica. Recombinant EhCP5 expressed in Pichia pastoris had kinetic properties similar to those of the native enzyme with respect to substrate specificity and sensitivity to proteinase inhibitors. In contrast to the activation of proIL-1beta by amebic lysates, the purified proteinase cleaved proIL-18 and mature IL-18 to biologically inactive fragments. These studies suggest that the acute host response and amebic invasion result from a complex interplay of parasite virulence factors and host defenses. E. histolytica may block the host inflammatory response by a novel mechanism, inactivation of IL-18.

Journal ArticleDOI
TL;DR: IL‐18 selectively up‐regulates the expression of ICAM‐1 on monocytes, and this contributes to the proinflammatory effects of this cytokine.
Abstract: Induction of expression of adhesion molecules is a crucial step in inflammation. The role of interleukin-18 (IL-18) in induction of various adhesion molecules was investigated in freshly isolated peripheral blood mononuclear cells and human monocyte and T-cell lines. IL-18 selectively up-regulated intercellular adhesion molecule-1 (ICAM-1) expression on freshly isolated human monocytes, but not on lymphocytes. The expression of other adhesion molecules was not influenced. Induction of ICAM-1 by IL-18 was dependent on endogenous tumour necrosis factor-alpha (TNF-alpha), and IL-12 had an additive effect on that of IL-18. No changes in adhesion molecule expression were observed on the monocytic cell line THP-1 and on the T-cell lines HSB-2 and Jurkat J16. In addition, induction of ICAM-1 on monocytes by lipopolysaccharide was slightly, but significantly, inhibited by blockade of either endogenous IL-18 or TNF-alpha with IL-18 binding protein or TNF binding protein, respectively. Blocking IL-1 effects with IL-1 receptor antagonist did not influence ICAM-1 levels. In conclusion, IL-18 selectively up-regulates the expression of ICAM-1 on monocytes, and this contributes to the proinflammatory effects of this cytokine.


Journal ArticleDOI
TL;DR: In uremia, retention of IL-18BP does not suffice to neutralize most of the concomitantly raised levels of totalIL-18 resulting in elevated levels of free IL- 18, and suppression of IFNgamma production in uremIA may be due to inhibitors of IFngammaProduction other than IL-17BP.
Abstract: UNLABELLED Uremia is associated with suppressed cellular immune responses, manifested, in part, by impaired interferon-gamma (IFNgamma) production. We investigated the influence of kidney function on plasma levels of interleukin-18 binding protein (IL-18BP), the naturally occurring inhibitor of IL-18. METHODS Plasma levels of IL-18, IL-18BP and IFNgamma were measured by specific immunoassays in patients with normal kidney function (NKF, n = 29), in patients with chronic renal insufficiency (CRI, n = 29), and in patients on hemodialysis (HD, n = 40). In addition, Staphylococcus epidermidis-induced production of IFNgamma and IL-18 in whole blood cultures was determined in 12 patients on HD and compared to production in 9 controls with NKF. RESULTS Plasma IL-18 (mean +/- SEM) in NKF was 17.9 +/- 3.6 pg/ml, in CR142.6 +/- 7.0 pg/ml (p < 0.01), and in HD 93.5 +/- 13.6 pg/ml (p < 0.001). The level of IL-18BP in NKF was 3.4 +/- 0.4 ng/ml, in CRI 7.5 +/- 0.7 ng/ml (p < 0.001), and in HD 13.1 +/- 0.8 ng/ml (p < 0.001). Plasma IL-18BP was inversely correlated with creatinine clearance (correlation coefficient: -0.7479). The level of free IL-18 was calculated in NKF to be 13.8 +/- 3.3 pg/ml, in CRI 23.6 +/- 3.9 pg/ml (not significant), and in HD 39.6 +/- 5.9 pg/ml (p < 0.001). Stimulated whole blood production of IFNgamma in NKF was 185 +/- 74 pg/10(6) mononuclear cells (PBMC), but suppressed in HD to 27.3 +/- 16 pg/10(6) PBMC (p < 0.05). CONCLUSION In uremia, retention of IL-18BP does not suffice to neutralize most of the concomitantly raised levels of total IL-18 resulting in elevated levels of free IL-18. Nevertheless, IFNgamma production in whole blood is reduced in patients on HD. Therefore, suppression of IFNgamma production in uremia may be due to inhibitors of IFNgamma production other than IL-18BP.

Journal ArticleDOI
TL;DR: Results indicate that high endogenous levels of IL‐18BP in trangenic mice effectively neutralizeIL‐18 and are protective in response to different inflammatory stimuli.
Abstract: Interleukin (IL)-18 binding protein (IL-18BP) is a natural inhibitor of the pleiotropic cytokine IL-18. To study the role of IL-18BP in modulating inflammatory responses in vivo, mice transgenic for human IL-18BP isoform a (IL-18BP-Tg) were generated. The transgene was expressed at high levels in each organ examined. High levels of bioactive human IL-18BPa were detectable in the circulation of IL-18BP-Tg mice, which were viable, fertile, and had no tissue or organ abnormality. The high levels of IL-18BP in the transgenic mice were able to completely neutralize the interferon-gamma (IFN-gamma)-inducing activity of exogenously administered IL-18. Following administration of endotoxin, with or without prior sensitization with heat-inactivated Propionibacterium acnes, IL-18BP-Tg mice produced significantly lower serum levels of IFN-gamma and macrophage-inflammatory protein-2 compared with nontransgenic littermates. Significantly reduced production of IFN-gamma in response to endotoxin was also observed in cultures of IL-18BP-Tg splenocytes. Finally, IL-18BP-Tg mice were completely protected in a model of hepatotoxicity induced by administration of concanavalin A. These results indicate that high endogenous levels of IL-18BP in trangenic mice effectively neutralize IL-18 and are protective in response to different inflammatory stimuli.

Journal ArticleDOI
TL;DR: A new class of anti-cytokine that may bypass problems with rheumatoid arthritis and other autoimmune disorders appears on the horizon.
Abstract: Agents that block the action of specific cytokines have changed the lives of many patients with rheumatoid arthritis and other autoimmune disorders. But frequent self-injections or injections by a physician during a clinic visit are required. Now a new class of anti-cytokine that may bypass such problems appears on the horizon ( pages 47–52 ).

Journal ArticleDOI
TL;DR: The present studies demonstrate that the biologically active IL-18R complex requires the membrane-proximal third Ig-like domain in IL- 18Rα for the formation of IL-16R ternary complex as well as for signal transduction involved inIL-18-induced IFN-γ in NK cells.
Abstract: Steady state mRNA levels in various human tissues reveal that the proinflammatory cytokine IL-18 is constitutively and ubiquitously expressed. However, limited IL-18R alpha-chain (IL-18Ralpha) expression in tissues may restrict ligand-acting sites and contribute to a specific response for IL-18. To study the IL-18R complex, [(125)I]IL-18 was studied for binding to the cell surface receptors of IL-18-responsive NK and macrophagic KG-1 cells. After cross-linking, [(125)I]IL-18 formed three IL-18R complexes with sizes of approximately 93, 160, and 220 kDa. In KG-1 cells, Scatchard analysis revealed the presence of 135 binding sites/cell, with an apparent dissociation constant (K(d)) of 250 pM; in NK cells, there were 350 binding sites per cell with an apparent K(d) of 146 pM. Each domain of extracellular IL-18Ralpha was cloned and individually expressed in Escherichia coli. An mAb specifically recognized the membrane-proximal third domain; this mAb blocked IL-18-induced IFN-gamma production in NK cells. Furthermore, deletion of the membrane-proximal third domain of IL-18Ralpha prevented the formation of IL-18R ternary complex with IL-18R beta-chain. The present studies demonstrate that the biologically active IL-18R complex requires the membrane-proximal third Ig-like domain in IL-18Ralpha for the formation of IL-18R ternary complex as well as for signal transduction involved in IL-18-induced IFN-gamma in NK cells.

Journal ArticleDOI
TL;DR: The biology of IL-18 andIL-18BP, a glycoprotein of 40,000 daltons, which is constitutively expressed and appears to be the natural inhibitor of Il-18 activity, is reviewed here in the context of the immunosuppression of chronic renal failure.
Abstract: Although interleukin (IL)-18 is a member of the IL-1 family of ligands, IL-18 appears to have unique characteristics, particularly in the regulation of the T helper type 1 (Th1) response. Th1 response

Journal ArticleDOI
21 Jan 2003-Cytokine
TL;DR: S. epidermidis stimulates IFN-gamma which is IL-18, IL-12 and TNF-dependent, but IL-1 independent, according to the relative contributions of these cytokines by the Gram-positive bacterium Staphylococcus epiderMidis.

Journal ArticleDOI
TL;DR: Compared to low-flux polysulfone HD with ultrafiltered dialysate, high- flux HD with the synthetic Helixone® membrane did not result in a significant change in plasma levels of proinflammatory and anti-inflammatory cytokines, but restores whole blood IFN-γ production without significant changes in free IL-18.
Abstract: Long-term hemodialysis (HD) induces an inflammatory response and is associated with a suppressed cellular immune response manifested, in part, by impaired interferon (IFN-γ) production. We investigate

Book ChapterDOI
01 Jan 2003
TL;DR: The most relevant properties of IL-1 in inflammation are the initiation of cyclooxygenase type 2 (COX-2), type 2 phospholipase A, and inducible nitric oxide synthase (iNOS) as mentioned in this paper.
Abstract: IL-2 and cytokines affect lymphocyte function, and lymphocyte expansion, IL-1 and its related family members are primarily proinflammatory cytokines by their ability to stimulate the expression of genes associated with inflammation, and autoimmune diseases. The relevant properties of IL-1 in inflammation are the initiation of cyclooxygenase type 2 (COX-2), type 2 phospholipase A, and inducible nitric oxide synthase (iNOS). This accounts for the large amount of prostaglandin-E2 (PGE2), platelet activating factor, and nitric oxide (NO) produced by cells exposed to IL-1 or in animals or humans injected with IL-1. Another important proinflammatory property of IL-1 is its ability to increase the expression of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), on mesenchymal cells, and vascular-cell adhesion molecule-1 (VCAM-1) on endothelial cells. The latter property promotes the infiltration of inflammatory and immunocompetent cells into the extravascular space. IL-1 is also an angiogenic factor by increasing the expression of vascular endothelial growth factor. It plays a role in tumor metastasis and blood vessel supply. The strongest case for the importance of IL-1 in disease processes comes from the administration of the IL-1 receptor antagonist, a member of the IL-1 family that prevents IL-1 activity. In addition to proinflammatory properties, IL-1 is also an adjuvant during antibody production, and acts on bone marrow stem cells for differentiation in the myeloid series. IL-1 was administered to humans in order to reduce the nadir of white blood cells, and platelets of patients undergoing bone marrow transplantation.

Journal Article
TL;DR: In this article, the authors investigated the influence of treatment of wild type mice with recombinant human IL-1 receptor antagonist (IL•1ra) which resulted in an incomplete and transient inhibition of IL•1 activity.
Abstract: The inhibition of the biological activity of IL‐1 by recombinant human IL‐1 receptor antagonist (IL‐1ra) has been investigated in several, controlled clinical trials. Encouraging results have been reported, in particular in patients with rheumatoid arthritis. In the present study, we investigated the influence of treatment of wild type mice with IL‐1ra, which resulted in an incomplete and transient inhibition of IL‐1 activity. Treatment with recombinant human IL‐1ra resulted in an enhanced bacterial outgrowth in the lungs of BALB\c and C57BL\6 mice early after induction of pneumococcal pneumonia, without influencing survival or the pulmonary inflammatory response. The effect of IL‐1ra on the host response to S. pneumoniae pneumonia is modest and transient. The present data, together with the findings in IL‐1R\ mice in earlier work, suggest that IL‐1 occupies a role in the pulmonary immune response to S. pneumoniae that is substantially less prominent than that of TNF‐α.

Journal ArticleDOI
TL;DR: In vitro findings indicate that C. pneumoniae is more than an innocent bystander, rather it is a pathophysiologic participant in atherogenesis warranting elimination, and promoted release of prototypical atherogenic cytokines.

Journal ArticleDOI
TL;DR: It is concluded that IL18BP does not contribute to the overall genetic susceptibility to type 1 diabetes and none of these were frequent enough to permit association studies in T1DM.
Abstract: Type 1 (insulin-dependent) diabetes, T1DM, is the result of an immune-mediated destruction of the pancreatic beta cells dependent mainly on T helper cells and macrophages. Interleukin-18 (IL-18) is a proinflammatory cytokine produced mainly by macrophages. IL-18 is capable of inducing T lymphocyte synthesis of IFNgamma, thereby skewing the T helper response toward a T helper type 1 (Th1) profile. IL-18 binding protein (IL18BP) neutralizes IL-18 and leads to a reduced Th1 response. Polymorphisms in IL18BP may affect the activity of IL-18 and the magnitude of the Th1 response and may play a role in the pathogenesis of T1DM. The aim of the study was therefore to identify polymorphisms in IL18BP and to test these for association with T1DM. We evaluated the human IL18BP gene on chromosome 11q13 as a candidate susceptibility gene for T1DM and scanned the entire IL18BP (promoter, exons 1-6, and 3'UTR) for polymorphisms using single-strand conformational polymorphism analysis and direct sequencing. We identified a total of 11 polymorphisms, all having allele frequencies ranging between 0.05 and 0.10. Four were in the 5'UTR: -257G-->T, -78C-->T, -65G-->A, and -59A-->G. Three were in intron 3: IVS3+140A-->C, IVS4-147G-->T, and IVS4-59G-->T. The last four, 38*A-->T, 48*T-->A, 388*C-->G, and 440*_441*insG, were in the 3'UTR of IL18BP. However, none of these were frequent enough to permit association studies in T1DM and we conclude that IL18BP does not contribute to the overall genetic susceptibility to type 1 diabetes.

Book ChapterDOI
01 Jan 2003
TL;DR: Although the physiological response of the host to Gram negative and Gram positive sepsis may appear similar, the early inflammatory and immunological response to these pathogens seems to significantly differ depending upon the inciting organism.
Abstract: In the present study, we examine the diversity in host response to Gram negative and Gram positive pathogens by focusing on the differential proinflammatory cytokine responses in the plasma of septic patients. Moreover, a genome-wide survey of gene expression pattern was performed on whole blood from human volunteers stimulated ex vivo with Gram negative and Gram positive microbial products. Blood plasma was obtained from 52 patients with Gram negative or Gram positive sepsis on admission and evaluated for proinflammatory cytokine concentrations. In addition, whole blood from healthy human volunteers was stimulated ex vivo with E. coli lipopolysaccharide (LPS) or heat-killed Staphylococcus aureus (SAC). Gene expression pattern were also obtained from ex vivo stimulated whole blood leukocytes using GeneChip technology. Plasma concentrations of TNF-α, IL-1 Ra, IL-8, IL-10, IL-18BP, procalcitonin, and protein C did not differ between patients with Gram negative and Gram positive sepsis. However, plasma IL-1s and IL-18 concentrations were significantly higher in patients with Gram positive sepsis. Ex vivo stimulation of whole blood with SAC markedly increased IL-1s and IL-18 compared to LPS stimulation. GeneChip technology supervised analysis revealed 758 cross-validated probe sets (genes) that are capable of accurately discriminating among Gram negative-stimulated, Gram positive-stimulated, and unstimulated whole blood leukocytes. Furthermore, of these 758 genes, only 87 were upregulated in both conditions greater than 2-fold and only 43 genes were commonly down- regulated. Although the physiological response of the host to Gram negative and Gram positive sepsis may appear similar, the early inflammatory and immunological response to these pathogens seems to significantly differ depending upon the inciting organism.