Interleukin-1β-regulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behcet's disease: an open-label pilot study.

Objective: Uveitis and retinal vasculitis are sight-threatening manifestations of Behçet's disease with limited treatment options. This pilot study aimed to evaluate the safety, pharmacokinetics and clinical activity of XOMA 052 (gevokizumab), a recombinant humanised anti-interleukin 1β antibody, in Behçet's disease patients with uveitis.

Methods: Patients with acute posterior or panuveitis, and/or retinal vasculitis, resistant to azathioprine and/or ciclosporin, and receiving 10 mg/day or less of prednisolone, were enrolled into the 98-day study.

Eukaryotic translation initiation factor 5A small interference RNA-liposome complexes reduce inflammation and increase survival in murine models of severe sepsis and acute lung injury.

Background: Many novel therapeutics have failed to reduce all-cause mortality associated with severe sepsis. Eukaryotic translation initiation factor 5A (eIF5A) is a regulator of apoptosis as well as inflammatory cell activation, making it a potential target for sepsis therapy.

Methods: In a murine model of severe sepsis, mice were intraperitoneally challenged with lipopolysaccharide (LPS).

Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney.

We have demonstrated that caspase-1-deficient (caspase-1(-/-)) mice are functionally and histologically protected against cisplatin-induced acute renal failure (ARF). Caspase-1 exerts proinflammatory effects via the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil recruitment. We sought to determine the role of the cytokines IL-1beta, IL-18, and IL-6 and neutrophil recruitment in cisplatin-induced ARF.

Pentoxifylline protects against endotoxin-induced acute renal failure in mice.

Acute renal failure (ARF) in septic patients drastically increases the mortality to 50-80%. Sepsis induces several proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), a major pathogenetic factor in septic ARF. Pentoxifylline has several functions including downregulation of TNF-alpha and endothelia-dependent vascular relaxation.

Soluble human p55 and p75 tumor necrosis factor receptors reverse spontaneous arthritis in transgenic mice expressing transmembrane tumor necrosis factor alpha.

Objective: The roles of the transmembrane and secreted forms of tumor necrosis factor alpha (TNFalpha) in rheumatoid arthritis (RA) remain unclear. Agents used to inhibit TNFalpha have shown varying efficacy in RA patients, suggesting that anti-TNFalpha agents possess dissimilar mechanisms of action, including the ability to neutralize transmembrane (tmTNFalpha) and secreted TNFalpha. In this study, TNFalpha-knockout (TNFalpha-KO) mice that were genetically altered to express elevated levels of tmTNFalpha were constructed to further understand the roles of the 17-kd secreted, trimeric, and 26-kd transmembrane forms of TNFalpha.

Melanoma inhibits macrophage activation by suppressing toll-like receptor 4 signaling.

Background: Activated macrophages defend against tumors by secreting cytokines to recruit secondary immune cells, presenting antigen to T cells, and by direct tumor cytotoxicity. Peritoneal macrophages harvested from melanoma-bearing mice are less cytotoxic to melanoma cells, and produce less superoxide, nitric oxide, and tumor necrosis factor-alpha (TNF-alpha) than those from nontumor-bearing mice. Similar impairment of macrophage activation occurs in vitro using media harvested from cultured melanoma cells.

Endotoxemic acute renal failure is attenuated in caspase-1-deficient mice.

Caspase-1-deficient (-/-) mice are protected against sepsis-induced hypotension and mortality. We investigated the role of caspase-1 and its associated cytokines in a nonhypotensive model of endotoxemic acute renal failure (ARF). Mice were injected intraperitoneally with 2.

Caspase-1-deficient mice are protected against cisplatin-induced apoptosis and acute tubular necrosis.

Background: Cisplatin is a commonly used chemotherapeutic agent which causes apoptosis or necrosis of renal tubular epithelial cells in vitro. Caspases are a family of cysteine proteases that mediate apoptosis (caspase-3) and inflammation (caspase-1). Although well studied in vitro, caspases have not been previously studied in cisplatin-induced acute renal failure (ARF) in vivo.

Interleukin-10 attenuates the response to vascular injury.

Background: The inflammatory response to vascular injury is characterized by expression of cytokines, growth factors, and chemokines that conspire to promote vessel remodeling and intimal hyperplasia (IH). Interleukin-10 (IL-10) is a multifunctional cytokine that has several anti-inflammatory properties in vitro. Few studies have evaluated the effects of IL-10 in experimental atherosclerosis.

Differences in signaling pathways by IL-1beta and IL-18.

IL-1 and IL-18 are members of the IL-1 family of ligands, and their receptors are members of the IL-1 receptor family. Although several biological properties overlap for these cytokines, differences exist. IL-18 uniquely induces IFN-gamma from T lymphocytes and natural killer cells but does not cause fever, whereas fever is a prominent characteristic of IL-1 in humans and animals.

Hemorrhage-induced acute lung injury is TLR-4 dependent.

Toll-like receptor 4 (TLR-4), initially identified as an LPS receptor, is critical to the signaling of a variety of danger signals, including heat shock protein 60, fibrinogen, and fibronectin. Recent data also suggest that TLR-4 plays a role in determining survival in both endotoxemia and hemorrhagic shock. We hypothesized that a functional TLR-4 would be required for hemorrhage and endotoxin-induced acute lung injury.

Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect.

Acute graft-versus-host disease (GVHD) and leukemic relapse are the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT), an effective therapy for hematological malignancies. Several studies have demonstrated that the dysregulation of proinflammatory cytokines and the loss of gastrointestinal tract integrity contribute to GVHD, whereas the donor cytotoxic responses are critical for graft-versus-leukemia (GVL) preservation. Suberoylanilide hydroxamic acid (SAHA) is currently in clinical trials as an antitumor agent; it inhibits the activity of histone deacetylases and at low doses exhibits antiinflammatory effects by reducing the production of proinflammatory cytokines.

Atherogenic effects of Chlamydia pneumoniae: refuting the innocent bystander hypothesis.

Objective: Serologic evidence of Chlamydia pneumoniae infection and atherosclerosis was first demonstrated in patients with ischemic heart disease in 1988. Subsequently, the organism has been detected in several cardiovascular lesions. Outside of observational reports, few studies mechanistically link vascular infection with C.

Regulation of Staphylococcus epidermidis-induced IFN-gamma in whole human blood: the role of endogenous IL-18, IL-12, IL-1, and TNF.

Interleukin 12 (IL-12) and IL-18 act synergistically to stimulate interferon gamma (IFN-gamma) production; moreover, IL-1 and tumor necrosis factor (TNF) may also augment IFN-gamma synthesis. We have investigated the relative contributions of these cytokines in the production of IFN-gamma and TNF by the Gram-positive bacterium Staphylococcus epidermidis, using the specific cytokine inhibitors IL-18 binding protein (IL-18BP), IL-1 receptor antagonist (IL-1Ra), anti-IL-12 antibodies (anti-IL-12 Ab), and TNF binding protein. Inhibition of caspase-1 reduced IFN-gamma and IL-1beta levels (by 80 and 67%, respectively) when heat-killed S.

Relative contribution of the TNF-alpha receptors to murine intimal hyperplasia.

Tumor necrosis factor-alpha (TNF-alpha) is an important mediator in the inflammatory response to vascular injury. The present study sought to determine the relative contribution of each TNF-alpha receptor subtype (p55 and p75) to intimal hyperplasia (IH) and characterize the mechanisms of transcriptional regulation after vascular injury. A murine model of wire carotid arterial injury was employed to induce IH in wild-type (WT), p55-deficient (p55-/-), and p75-deficient (p75-/-) mice.

A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity.

IL-1F7 was discovered in expressed sequence tag databases as a member of the increasing family of proteins sharing sequence homology to IL-1alpha/beta, IL-1Ra, and IL-18. In the present study using immunohistochemical staining, IL-1F7 was localized in human peripheral monocytic cells, suggesting its role in immune regulation. Recombinant human IL-1F7b was shown to bind to the IL-18Ralpha but without IL-18 agonistic or antagonistic function.

Lack of TNF-alpha attenuates intimal hyperplasia after mouse carotid artery injury.

This study sought to determine the influence of tumor necrosis factor-alpha (TNF-alpha) on intimal hyperplasia (IH) and characterize the mechanisms of transcriptional regulation after vascular injury. A murine model of wire carotid artery injury was employed to induce IH in wild-type (WT) and TNF-alpha-deficient [TNF(-/-)] animals. Three days after injury, TNF-alpha and nuclear factor-kappaB (NF-kappaB) protein expression was markedly increased in the injured WT carotid artery compared to control.

Interleukin-11 attenuates human vascular smooth muscle cell proliferation.

Interleukin (IL)-11 is a growth factor for megakaryocytes, osteoclasts, and intestinal mucosa. IL-11 is also an anti-inflammatory agent, mediating many of its effects by inhibition of the transcriptional activator nuclear factor (NF)-kappa B. The purposes of this study were to examine the effects of IL-11 on human vascular smooth muscle cell (VSMC) proliferation and NF-kappa B activity.

The combination of soluble IL-18Ralpha and IL-18Rbeta chains inhibits IL-18-induced IFN-gamma.

Although the beta chain of interleukin-18 receptor (IL-18Rbeta) is required for signaling, the soluble (extracellular) form does not bind IL-18, and its role in inhibiting IL-18 is unclear. In the present study, both the soluble human IL-18 ligand binding alpha chain (sIL-18Ralpha) and the sIL-18Rbeta chain were investigated for inhibition of IL-18-induced interferon-gamma (IFN-gamma) production in human peripheral blood mononuclear cells (PBMC), whole blood, and KG-1 macrophage and natural killer (NK) cell lines. Neutralization of IL-18 by soluble receptors was compared with that of the IL-18 binding protein (IL-18BP).

The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines.

Suberoylanilide hydroxamic acid (SAHA) is a hydroxamic acid-containing hybrid polar molecule; SAHA specifically binds to and inhibits the activity of histone deacetylase. Although SAHA, like other inhibitors of histone deacetylase, exhibits antitumor effects by increasing expression of genes regulating tumor survival, we found that SAHA reduces the production of proinflammatory cytokines in vivo and in vitro. A single oral administration of SAHA to mice dose-dependently reduced circulating TNF-alpha, IL-1-beta, IL-6, and IFN-gamma induced by lipopolysaccharide (LPS).

Ischemia alone is sufficient to induce TNF-alpha mRNA and peptide in the myocardium.

Over-production of tumor necrosis factor-alpha (TNF-alpha) following myocardial ischemia-reperfusion contributes to cardiac dysfunction, and anti-TNF-alpha has therapeutic potential for myocardial protection in cardiac surgery with obligatory ischemia. It remains unclear, however, whether myocardial TNF-alpha production occurs during ischemia and whether cardiac myocytes constitute a source of myocardial TNF-alpha. Ischemia alone has been shown to activate myocardial NF-kappaB.