Showing papers by "Charles A. Dinarello published in 2012"

Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases

Abstract: Interleukin-1 (IL-1) is a highly active pro-inflammatory cytokine that lowers pain thresholds and damages tissues. Monotherapy blocking IL-1 activity in autoinflammatory syndromes results in a rapid and sustained reduction in disease severity, including reversal of inflammation-mediated loss of sight, hearing and organ function. This approach can therefore be effective in treating common conditions such as post-infarction heart failure, and trials targeting a broad spectrum of new indications are underway. So far, three IL-1-targeted agents have been approved: the IL-1 receptor antagonist anakinra, the soluble decoy receptor rilonacept and the neutralizing monoclonal anti-IL-1β antibody canakinumab. In addition, a monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1α antibody are in clinical trials.

IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist

Abstract: The functional role of IL-1 family member 10, recently renamed IL-38, remains unknown. In the present study we aimed to elucidate the biological function of IL-38 and to identify its receptor. Heat-killed Candida albicans was used to stimulate memory T-lymphocyte cytokine production in freshly obtained human peripheral blood mononuclear cells from healthy subjects. The addition of recombinant IL-38 (152 amino acids) inhibited the production of T-cell cytokines IL-22 (37% decrease) and IL-17 (39% decrease). The reduction in IL-22 and IL-17 caused by IL-38 was similar to that caused by the naturally occurring IL-36 receptor antagonist (IL-36Ra) in the same peripheral blood mononuclear cells cultures. IL-8 production induced by IL-36γ was reduced by IL-38 (42% decrease) and also was reduced by IL-36Ra (73% decrease). When human blood monocyte-derived dendritic cells were used, IL-38 as well as IL-36Ra increased LPS-induced IL-6 by twofold. We screened immobilized extracellular domains of each member of the IL-1 receptor family, including the IL-36 receptor (also known as “IL-1 receptor-related protein 2”) and observed that IL-38 bound only to the IL-36 receptor, as did IL-36Ra. The dose–response suppression of IL-38 as well as that of IL-36Ra of Candida-induced IL-22 and IL-17 was not that of the classic IL-1 receptor antagonist (anakinra), because low concentrations were optimal for inhibiting IL-22 production, whereas higher concentrations modestly increased IL-22. These data provide evidence that IL-38 binds to the IL-36R, as does IL-36Ra, and that IL-38 and IL-36Ra have similar biological effects on immune cells by engaging the IL-36 receptor.

Effects of Gevokizumab on Glycemia and Inflammatory Markers in Type 2 Diabetes

Abstract: OBJECTIVE: Metabolic activation of the innate immune system governed by interleukin (IL)-1beta contributes to beta-cell failure in type 2 diabetes. Gevokizumab is a novel, human-engineered monoclonal anti-IL-1beta antibody. We evaluated the safety and biological activity of gevokizumab in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a placebo-controlled, dose-escalation study, a total of 98 patients were randomly assigned to placebo (17 subjects) or gevokizumab (81 subjects) at increasing doses and dosing schedules. The primary objective of the study was to evaluate the safety profile of gevokizumab in type 2 diabetes. The secondary objectives were to assess pharmacokinetics for different dose levels, routes of administration, and regimens and to assess biological activity. RESULTS: The study drug was well tolerated with no serious adverse events. There was one hypoglycemic event whereupon concomitant insulin treatment had to be reduced. Clearance of gevokizumab was consistent with that for a human IgG(2), with a half-life of 22 days. In the combined intermediate-dose group (single doses of 0.03 and 0.1 mg/kg), the mean placebo-corrected decrease in glycated hemoglobin was 0.11, 0.44, and 0.85% after 1, 2 (P = 0.017), and 3 (P = 0.049) months, respectively, along with enhanced C-peptide secretion, increased insulin sensitivity, and a reduction in C-reactive protein and spontaneous and inducible cytokines. CONCLUSIONS: This novel IL-1beta-neutralizing antibody improved glycemia, possibly via restored insulin production and action, and reduced inflammation in patients with type 2 diabetes. This therapeutic agent may be able to be used on a once-every-month or longer schedule.

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

Abstract: Objective Uveitis and retinal vasculitis are sight-threatening manifestations of Behcet9s 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 Behcet9s 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. Immunosuppressive agents were discontinued at baseline. Patients received a single infusion of XOMA 052 (0.3 mg/kg). The safety and uveitis status and pharmacokinetics of XOMA 052 were evaluated. Results Seven patients enrolled and completed the study. No treatment-related adverse event was observed. XOMA 052 treatment was associated with rapid and durable clinical response in all patients. Complete resolution of intraocular inflammation was achieved in 4–21 days (median 14 days), with a median duration of response of 49 days (range 21–97 days); one patient remained exacerbation free throughout the study. Conclusions Well tolerated, XOMA 052 resulted in a rapid onset and sustained reduction in intraocular inflammation in patients with resistant uveitis and retinal vasculitis. Moreover, the effect was observed despite discontinuation of immunosuppressive agents and without the need to increase corticosteroid dosages.

Enhanced Interleukin-1 Activity Contributes to Exercise Intolerance in Patients with Systolic Heart Failure

Abstract: BACKGROUND: Heart failure (HF) is a complex clinical syndrome characterized by impaired cardiac function and poor exercise tolerance. Enhanced inflammation is associated with worsening outcomes in HF patients and may play a direct role in disease progression. Interleukin-1beta (IL-1beta) is a pro-inflammatory cytokine that becomes chronically elevated in HF and exerts putative negative inotropic effects. METHODS AND RESULTS: We developed a model of IL-1beta-induced left ventricular (LV) dysfunction in healthy mice that exhibited a 32% reduction in LV fractional shortening (P<0.001) and a 76% reduction in isoproterenol response (P<0.01) at 4 hours following a single dose of IL-1beta 3 mcg/kg. This phenotype was reproducible in mice injected with plasma from HF patients and fully preventable by pretreatment with IL-1 receptor antagonist (anakinra). This led to the design and conduct of a pilot clinical to test the effect of anakinra on cardiopulmonary exercise performance in patients with HF and evidence of elevated inflammatory signaling (n = 7). The median peak oxygen consumption (VO(2)) improved from 12.3 [10.0, 15.2] to 15.1 [13.7, 19.3] mL . kg(-1) . min(-1) (P = 0.016 vs. baseline) and median ventilator efficiency (V(E)/VCO(2) slope) improved from 28.1 [22.8, 31.7] to 24.9 [22.9, 28.3] (P = 0.031 vs. baseline). CONCLUSIONS: These findings suggest that IL-1beta activity contributes to poor exercise tolerance in patients with systolic HF and identifies IL-1beta blockade as a novel strategy for pharmacologic intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT01300650.

Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation.

Abstract: Acute graft-versus-host disease (GvHD) is a major complication that prevents successful outcomes after allogeneic bone marrow transplantation (BMT), an effective therapy for hematological malignancies. Several studies demonstrate that donor T cells and host antigen-presenting cells along with several proinflammatory cytokines are required for the induction of GvHD and contribute to its severity. Increasing evidence demonstrates that human serum-derived αalpha-1- anti-trypsin (AAT) reduces production of proinflammatory cytokines, induces anti-inflammatory cytokines, and interferes with maturation of dendritic cells. Using well-characterized mouse models of BMT, we have studied the effects of AAT on GvHD severity. Administration of AAT early after BMT decreased mortality in three models of GvHD and reduced serum levels of proinflammatory cytokines in the allogeneic recipients compared with vehicle (albumin) treated animals. AAT treatment reduced the expansion of alloreactive T effector cells but enhanced the recovery of T regulatory T cells, (Tregs) thus altering the ratio of donor T effector to T regulatory cells in favor of reducing the pathological process. However, despite altering the ratio in vivo, AAT had no direct effects on either the donor T effector cells or T regulatory cells Tregs in vitro. In contrast, AAT suppressed LPS-induced in vitro secretion of proinflammatory cytokines such as TNF-α and IL-1β, enhanced the production of the anti-inflammatory cytokine IL-10, and impaired NF-κB translocation in the host dendritic cells. In light of its long history of safety in humans, these findings suggest that administration of AAT represents a novel unique and viable strategy to mitigate clinical GvHD.

Innate Immune Response of Human Alveolar Macrophages during Influenza A Infection

Abstract: Alveolar macrophages (AM) are one of the key cell types for initiating inflammatory and immune responses to influenza virus in the lung. However, the genome-wide changes in response to influenza infection in AM have not been defined. We performed gene profiling of human AM in response to H1N1 influenza A virus PR/8 using Affymetrix HG-U133 Plus 2.0 chips and verified the changes at both mRNA and protein levels by real-time RT-PCR and ELISA. We confirmed the response with a contemporary H3N2 influenza virus A/New York/238/2005 (NY/238). To understand the local cellular response, we also evaluated the impact of paracrine factors on virus-induced chemokine and cytokine secretion. In addition, we investigated the changes in the expression of macrophage receptors and uptake of pathogens after PR/8 infection. Although macrophages fail to release a large amount of infectious virus, we observed a robust induction of type I and type III interferons and several cytokines and chemokines following influenza infection. CXCL9, 10, and 11 were the most highly induced chemokines by influenza infection. UV-inactivation abolished virus-induced cytokine and chemokine response, with the exception of CXCL10. The contemporary influenza virus NY/238 infection of AM induced a similar response as PR/8. Inhibition of TNF and/or IL-1β activity significantly decreased the secretion of the proinflammatory chemokines CCL5 and CXCL8 by over 50%. PR/8 infection also significantly decreased mRNA levels of macrophage receptors including C-type lectin domain family 7 member A (CLEC7A), macrophage scavenger receptor 1 (MSR1), and CD36, and reduced uptake of zymosan. In conclusion, influenza infection induced an extensive proinflammatory response in human AM. Targeting local components of innate immune response might provide a strategy for controlling influenza A infection-induced proinflammatory response in vivo.

Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children

Abstract: Histone deacetylases (HDACs) are promising pharmacological targets in cancer and autoimmune diseases. All 11 classical HDACs (HDAC1–11) are found in the pancreatic beta cell, and HDAC inhibitors (HDACi) protect beta cells from inflammatory insults. We investigated which HDACs mediate inflammatory beta cell damage and how the islet content of these HDACs is regulated in recent-onset type 1 diabetes. The rat beta cell line INS-1 and dispersed primary islets from rats, either wild type or HDAC1–3 deficient, were exposed to cytokines and HDACi. Molecular mechanisms were investigated using real-time PCR, chromatin immunoprecipitation and ELISA assays. Pancreases from healthy children and children with type 1 diabetes were assessed using immunohistochemistry and immunofluorescence. Screening of 19 compounds with different HDAC selectivity revealed that inhibitors of HDAC1, -2 and -3 rescued INS-1 cells from inflammatory damage. Small hairpin RNAs against HDAC1 and -3, but not HDAC2, reduced pro-inflammatory cytokine-induced beta cell apoptosis in INS-1 and primary rat islets. The protective properties of specific HDAC knock-down correlated with attenuated cytokine-induced iNos expression but not with altered expression of the pro-inflammatory mediators Il1α, Il1β, Tnfα or Cxcl2. HDAC3 knock-down reduced nuclear factor κB binding to the iNos promoter and HDAC1 knock-down restored insulin secretion. In pancreatic sections from children with type 1 diabetes of recent onset, HDAC1 was upregulated in beta cells whereas HDAC2 and -3 were downregulated in comparison with five paediatric controls. These data demonstrate non-redundant functions of islet class I HDACs and suggest that targeting HDAC1 and HDAC3 would provide optimal protection of beta cell mass and function in clinical islet transplantation and recent-onset type 1 diabetic patients.

Neutrophil-Mediated Inhibition of Proinflammatory Cytokine Responses

Abstract: Neutrophils (polymorphonuclear neutrophils [PMNs]) play an elaborate role in the innate immune response against invading pathogens. Recent research provided evidence that PMNs can play a modulatory role in inflammation next to their primary role of phagocytosis. In the current study, we investigated whether neutrophils can modulate the innate immune response against Candida albicans. Production of the proinflammatory cytokines IL-1β and TNF-α by human PBMCs in response to C. albicans or LPS was decreased by coculture of PMNs; however, the anti-inflammatory cytokine IL-10 remained unaffected. Using Transwells and cells of patients with chronic granulomatous disease, we show that this downregulation of proinflammatory cytokine production was independent of phagocytosis and reactive oxygen species but was dependent on a soluble factor. We suggest that neutrophil-derived proteases are responsible for the downregulation of IL-1β and TNF-α, as cytokine production could be recovered by addition of α1-antitrypsin, an endogenous inhibitor of serine proteases. PMN lysates and neutrophil elastase could degrade recombinant human IL-1β and TNF-α but not IL-10, and this could be inhibited by addition of α1-antitrypsin. Moreover, we also provide evidence that the dampening effect of PMNs is present in vivo in a murine zymosan-induced arthritis model and a murine experimental endotoxemia model. Altogether, our data show that PMNs can dampen the proinflammatory response to C. albicans by protease-mediated degradation of cytokines. This observation suggest that PMNs might play a important regulatory role in the host defense against C. albicans and can be important for understanding the regulation of inflammation in general.

Protection from Inflammatory Organ Damage in a Murine Model of Hemophagocytic Lymphohistiocytosis Using Treatment with IL-18 Binding Protein

Abstract: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition due to the association of an infectious agent with lymphocyte cytotoxicity defects, either of congenital genetic origin in children or presumably acquired in adults. In HLH patients, an excess of lymphocyte or macrophage cytokines, such as IFN-γ and TNFα is present in serum. In animal models of the disease, IFN-γ and TNF-α have been shown to play a central pathogenic role. In humans, unusually high concentrations of IL-18, an inducer of IFN-γ and TNF-α have been reported, and are associated with an imbalance between IL-18 and its natural inhibitor IL-18 binding protein (IL-18BP) resulting in an excess of free IL-18. Here we studied whether IL-18BP could reduce disease severity in an animal model of HLH. Mouse cytomegalovirus infection in perforin-1 knock-out mice induced a lethal condition similar to human HLH characterized by cytopenia with marked inflammatory lesions in the liver and spleen as well as the presence of hemophagocytosis in bone marrow. IL-18BP treatment decreased hemophagocytosis and reversed liver as well as spleen damage. IL-18BP treatment also reduced both IFN-γ and TNF-α production by CD8+ T and NK cells, as well as Fas ligand expression on NK cell surface. These data suggest that IL-18BP is beneficial in an animal model of HLH and in combination with anti-infectious therapy may be a promising strategy to treat HLH patients.

Differential expression of interleukin‐32 in chronic rhinosinusitis with and without nasal polyps

Abstract: To cite this article: Keswani A, Chustz RT, Suh L, Carter R, Peters AT, Tan BK, Chandra R, Kim S-H, Azam T, Dinarello CA, Kern RC, Schleimer RP, Kato A. Differential expression of interleukin-32 in chronic rhinosinusitis with and without nasal polyps. Allergy 2012; 67: 25–32. Abstract Background: Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by local inflammation of the upper airways and sinuses and is frequently divided into polypoid CRS (CRSwNP) and nonpolypoid CRS (CRSsNP). However, the mechanism of inflammation in CRS has still not been fully elucidated. The aim of the study was to investigate the role of interleukin-32 (IL-32), a recently discovered proinflammatory cytokine, in CRS. Methods: We collected nasal epithelial cells and nasal tissue from patients with CRS and control subjects. We assayed mRNA for IL-32 by real-time PCR and measured IL-32 protein using ELISA, Western blot, and immunohistochemistry. Results: The expression of mRNA for IL-32 was elevated in epithelial cells from uncinate tissue from patients with CRSsNP compared with patients with CRSwNP (P < 0.05), control subjects (P = 0.06), and epithelial cells from nasal polyp (NP) tissue (P < 0.05). Production of IL-32 was induced by IFN-γ, TNF, and dsRNA in primary airway epithelial cells. In whole-tissue extracts, the expression of IL-32 protein was significantly elevated in patients with CRSwNP compared with patients with CRSsNP and control subjects. Immunohistochemistry data showed that IL-32 was detected in mucosal epithelial cells and inflammatory cells in the lamina propria. Levels of IL-32 were correlated with the levels of CD3 and macrophage mannose receptor in NP tissue. Immunofluorescence data showed IL-32 co-localization with CD3-positive T cells and CD68-positive macrophages in NPs. Conclusion: Overproduction of IL-32 may be involved in the pathogenesis of CRS, although the role of IL-32 in the inflammation in CRSsNP and CRSwNP may be different.

Combined anti-tumor necrosis factor-α therapy and DMARD therapy in rheumatoid arthritis patients reduces inflammatory gene expression in whole blood compared to DMARD therapy alone.

Abstract: Periodic assessment of gene expression for diagnosis and monitoring in rheumatoid arthritis (RA) may provide a readily available and useful method to detect subclinical disease progression and follow responses to therapy with disease modifying anti-rheumatic agents (DMARDs) or anti-TNF-α therapy. We used quantitative real-time PCR to compare peripheral blood gene expression profiles in active ("unstable") RA patients on DMARDs, stable RA patients on DMARDs, and stable RA patients treated with a combination of a disease-modifying anti-rheumatoid drug (DMARD) and an anti-TNF-α agent (infliximab or etanercept) to healthy human controls. The expression of 48 inflammatory genes were compared between healthy controls (N = 122), unstable DMARD patients (N = 18), stable DMARD patients (N = 26), and stable patients on combination therapy (N = 20). Expression of 13 genes was very low or undetectable in all study groups. Compared to healthy controls, patients with unstable RA on DMARDs exhibited increased expression of 25 genes, stable DMARD patients exhibited increased expression of 14 genes and decreased expression of five genes, and combined therapy patients exhibited increased expression of six genes and decreased expression of 10 genes. These findings demonstrate that active RA is associated with increased expression of circulating inflammatory markers whereas increases in inflammatory gene expression are diminished in patients with stable disease on either DMARD or anti-TNF-α therapy. Furthermore, combination DMARD and anti-TNF-α therapy is associated with greater reductions in circulating inflammatory gene expression compared to DMARD therapy alone. These results suggest that assessment of peripheral blood gene expression may prove useful to monitor disease progression and response to therapy.

Compositions, methods and uses of alpha 1-antitrypsin for early intervention in bone marrow transplantation and treatment of graft versus host disease

Abstract: Embodiments of the present invention relate to compositions and methods for treatment of subjects in need of or having a bone marrow transplant. Certain embodiments describe compositions and methods for treatment of conditions associated with bone marrow transplantations in a subject, for example, Graft versus Host Disease (GvHD) or bone marrow transplantation rejection. Some embodiments concern early or immediate bone marrow transplantation rejection. Certain embodiments relate to compositions and uses of alpha1-antitrypsin (α1-antitrypsin, AAT) and carboxyterminal peptide derivatives thereof and/or compositions and uses of serine protease inhibitors, immunomodulators or anti-inflammatory agent activity similar to that of AAT.

The lysine deacetylase inhibitor Givinostat inhibits β-cell IL-1β induced IL-1β transcription and processing.

Abstract: Aims: Pro-inflammatory cytokines and chemokines, in particular IL-1β, IFNγ, and CXCL10, contribute to β-cell failure and loss in DM via IL-1R, IFNγR, and TLR4 signaling. IL-1 signaling deficiency reduces diabetes incidence, islet IL-1β secretion, and hyperglycemia in animal models of diabetes. Further, IL-1R antagonism improves normoglycemia and β-cell function in type 2 diabetic patients. Inhibition of lysine deacetylases (KDACi) counteracts β-cell toxicity induced by the combination of IL-1 and IFNγ and reduces diabetes incidence in non-obese diabetic (NOD) mice. We hypothesized that KDACi breaks an autoinflammatory circuit by differentially preventing β-cell expression of the β-cell toxic inflammatory molecules IL-1β and CXCL10 induced by single cytokines. Results: CXCL10 did not induce transcription of IL-1β mRNA. IL-1β induced β-cell IL-1β mRNA and both IL-1β and IFNγ individually induced Cxcl10 mRNA transcription. Givinostat inhibited IL-1β-induced IL-1β mRNA expression in INS-1 and rat islets and IL-1β processing in INS-1 cells. Givinostat also reduced IFNγ induced Cxcl10 transcription in INS-1 cells but not in rat islets, while IL-1β induced Cxcl10 transcription was unaffected in both. Materials and Methods: INS-1 cells and rat islets of Langerhans were exposed to IL-1β, IFNγ or CXCL10 in the presence or absence of KDACi (givinostat). Cytokine and chemokine mRNA expressions were quantified by real-time qPCR, and IL-1β processing by western blotting of cell lysates. Conclusion/Interpretation: Inhibition of β-cell IL-1β expression and processing and Cxcl10 transcription contributes to the β-cell protective actions of KDACi. In vitro β-cell destructive effects of CXCL10 are not mediated via IL-1β transcription. The differential proinflammatory actions of KDACs may be attractive novel drug targets in DM.

Membrane interleukin-18 revisits membrane IL-1α in T-helper type 1 responses.

Abstract: Although all structural studies on cytokine-cytokine receptor interactions are based on a crystallized cytokine binding to its specific receptor, there is no dearth of evidence that membrane-embedded cytokines are biologically active by virtue of cell-cell contact. Clearly the orientation of the membrane cytokine is such that it allows binding to the receptor, as takes place with the soluble form of the cytokine. In this issue, Bellora et al. [Eur. J. Immunol. 2012. 42: 1618-1626] report that interleukin-18 (IL-18) exists as an integral membrane protein on M-CSF-differentiated human macrophages and that upon LPS stimulation, IL-18 induces IFN-gamma from NK cells in a caspase-1-dependent fashion. The immunological and inflammatory implications for this finding are considerable because of the role of IL-18 as the primary IFN-gamma inducing cytokine in promoting Th1 responses.

Grand Challenge in Inflammation

Abstract: Acute inflammation is a normal response to infection and is beneficial for the host to survive However, most human diseases are due to sterile inflammation When allowed to continue unchecked, sterile inflammation can result in autoinflammatory disorders, neurodegenerative disease, or cancer A variety of safe and effective anti-inflammatory agents are available for short term control of acute inflammation including aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) For the most part, even short term glucocorticoids are safe and effective But attacking the upstream causes of inflammation is required for long-term treatment There is new era of anti-inflammatory agents, which includes “biologicals” such as anti-cytokine therapies, kinase inhibitors, statins, histone deacetylase inhibitors, and PPAR agonists Reducing pain, inflammation, and fever with salicylate-containing plant extracts can be traced throughout written human history One hundred fifty years ago, Felix Hoffman acetylated salicylic acid and created aspirin Aspirin inhibits the cyclooxygenase (COX) enzymes COX-1 and COX-2, which synthesize the inflammatory mediators prostaglandins and thromboxanes The ability to block production of prostaglandins and thromboxanes accounts for aspirin being the world's most used therapeutic agent Second to aspirin are NSAIDs, which target COX-2 and hence the synthesis of prostaglandins, particularly PGE2 Synthetic forms of natural cortisol (termed glucocorticoids) are widely used to treat many inflammatory diseases and despite their serious side effects, glucocorticoids remain a mainstay of inflammation reduction Yet, it is still the challenge of the pharmaceutical chemist to develop more effective and less toxic agents to treat the signs and symptoms of acute inflammation as well as the long-term consequences of chronic inflammatory diseases Inflammation is a dynamic process with pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1 playing central roles A number of “biologicals” have been developed to treat inflammation by reducing the activity of specific cytokines or their receptors (anti-cytokine therapies), block lymphocyte trafficking into tissues, prevent the binding of monocyte–lymphocyte co-stimulatory molecules, or deplete B lymphocytes Current anti-cytokine therapies have found a place in the treatment of autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, and others Without question, neutralization of specific pro-inflammatory cytokines has demonstrated their causative role in inflammation and has changed the lives of millions of patients with these diseases One drawback of anti-cytokine therapies is decreased host immune defense against infection and possibly cancer Nevertheless, the benefits of anti-cytokine therapies outweigh the risks and the risks can be reduced Compared to the consequences of long-term glucocorticoid treatment to stem inflammation, anti-cytokine therapies are a major improvement Indeed, organ toxicities are rarely, if ever, observed with anti-cytokine therapies as they operate almost exclusively in extracellular rather than intracellular compartments Kinases that act downstream of cytokine receptors have become new targets to tame inflammation, and orally active small molecule inhibitors of intracellular signaling kinases will likely be the new frontier of anti-inflammatory agents However, because many intracellular signaling molecules are involved in normal cellular functions, the effective concentration that does not elicit organ toxicity will need to be carefully determined Statins, a safe class of drugs used for lowering serum cholesterol, also have anti-inflammatory properties Orally active inhibitors of histone deacetylases, which are currently in clinical use, are effective anti-inflammatory drugs Naturally occurring resolvins are also being developed as anti-inflammatory agents Thus the challenge is to develop anti-inflammatory agents that are orally active, safe, and effective for treating acute or chronic inflammation

Methods for treating cancer by regulation of tumor necrosis factor-alpha

Abstract: The present invention relates to compositions and methods relating to an interleukin18-inducible cytokine termed tumor necrosis factor-alpha inducing factor (TAIF) or interleukin-32 (IL-32). In particular, the present invention provides compositions and methods for treating autoimmune diseases and cancer, in part by regulation of tumor necrosis factor-alpha expression.