A novel TRIM22 gene polymorphism promotes the response to PegIFNα therapy through cytokine-cytokine receptor interaction signaling pathway in chronic hepatitis B.

IMPORTANCE: Pegylated interferon alfa (PegIFNα) has limited efficacy in the treatment of chronic hepatitis B (CHB). Although many biomarkers related to hepatitis B virus (HBV) have been proposed to stratify patients, the response rate to PegIFNα is still unsatisfactory. Herein, our data suggest that the single-nucleotide polymorphism (SNP) rs10838543 in TRIM22 potentiates a positive clinical response to PegIFNα treatment in patients with hepatitis B e antigen-positive CHB by increasing the levels of IFNL1, CCL3, and CCL5. These observations can help guide treatment decisions for patients with CHB to improve the response rate to PegIFNα.

Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia.

Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/ßc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/ßc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the individual cells in the AML hierarchy, in which high IL3Rα/ßc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance. SIGNIFICANCE: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. This article is highlighted in the In This Issue feature, p. 1749.

[Mechanism of artesunate on bone destruction in experimental rheumatoid arthritis based on transcriptomics and network pharmacology].

The present study investigated the mechanism of artesunate in the treatment of bone destruction in experimental rheumatoid arthritis(RA) based on transcriptomics and network pharmacology. The transcriptome sequencing data of artesunate in the inhibition of osteoclast differentiation were analyzed to obtain differentially expressed genes(DEGs). GraphPad Prism 8 software was used to plot volcano maps and heat maps were plotted through the website of bioinformatics. GeneCards and OMIM were used to collect information on key targets of bone destruction in RA. The DEGs of artesunate in inhibiting osteoclast differentiation and key target genes of bone destruction in RA were intersected by the Venny 2.1.0 platform, and the intersection target genes were analyzed by Gene Ontology(GO)/Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment. Finally, the receptor activator of nuclear factor-κB(RANKL)-induced osteoclast differentiation model and collagen-induced arthritis(CIA) model were established. Quantitative real time polymerase chain reaction(q-PCR), immunofluorescence, and immunohistochemistry were used to verify the pharmacological effect and molecular mechanism of artesunate in the treatment of bone destruction in RA. In this study, the RANKL-induced osteoclast differentiation model in vitro was established and intervened with artesunate, and transcriptome sequencing data were analyzed to obtain 744 DEGs of artesunate in inhibiting osteoclast differentiation. A total of 1 291 major target genes of bone destruction in RA were obtained from GeneCards and OMIM. The target genes of artesunate in inhibiting osteoclast differentiation and the target genes of bone destruction in RA were intersected to obtain 61 target genes of artesunate against bone destruction in RA. The intersected target genes were analyzed by GO/KEGG enrichment. According to the results previously reported, the cytokine-cytokine receptor interaction signaling pathway was selected for experimental verification. Artesunate intervention in the RANKL-induced osteoclast differentiation model showed that artesunate inhibited CC chemokine receptor 3(CCR3), CC chemokine receptor 1(CCR1) and leukemia inhibitory factor(LIF) mRNA expression in osteoclasts in a dose-dependent manner compared with the RANKL-induced group. Meanwhile, the results of immunofluorescence and immunohistochemistry showed that artesunate could dose-dependently reduce the expression of CCR3 in osteoclasts and joint tissues of the CIA rat model in vitro. This study indicated that artesunate regulated the CCR3 in the cytokine-cytokine receptor interaction signaling pathway in the treatment of bone destruction in RA and provided a new target gene for the treatment of bone destruction in RA.

Mechanism of artesunate on bone destruction in experimental rheumatoid arthritis based on transcriptomics and network pharmacology / 中国中药杂志

The present study investigated the mechanism of artesunate in the treatment of bone destruction in experimental rheumatoid arthritis(RA) based on transcriptomics and network pharmacology. The transcriptome sequencing data of artesunate in the inhibition of osteoclast differentiation were analyzed to obtain differentially expressed genes(DEGs). GraphPad Prism 8 software was used to plot volcano maps and heat maps were plotted through the website of bioinformatics. GeneCards and OMIM were used to collect information on key targets of bone destruction in RA. The DEGs of artesunate in inhibiting osteoclast differentiation and key target genes of bone destruction in RA were intersected by the Venny 2.1.0 platform, and the intersection target genes were analyzed by Gene Ontology(GO)/Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment. Finally, the receptor activator of nuclear factor-κB(RANKL)-induced osteoclast differentiation model and collagen-induced arthritis(CIA) model were established. Quantitative real time polymerase chain reaction(q-PCR), immunofluorescence, and immunohistochemistry were used to verify the pharmacological effect and molecular mechanism of artesunate in the treatment of bone destruction in RA. In this study, the RANKL-induced osteoclast differentiation model in vitro was established and intervened with artesunate, and transcriptome sequencing data were analyzed to obtain 744 DEGs of artesunate in inhibiting osteoclast differentiation. A total of 1 291 major target genes of bone destruction in RA were obtained from GeneCards and OMIM. The target genes of artesunate in inhibiting osteoclast differentiation and the target genes of bone destruction in RA were intersected to obtain 61 target genes of artesunate against bone destruction in RA. The intersected target genes were analyzed by GO/KEGG enrichment. According to the results previously reported, the cytokine-cytokine receptor interaction signaling pathway was selected for experimental verification. Artesunate intervention in the RANKL-induced osteoclast differentiation model showed that artesunate inhibited CC chemokine receptor 3(CCR3), CC chemokine receptor 1(CCR1) and leukemia inhibitory factor(LIF) mRNA expression in osteoclasts in a dose-dependent manner compared with the RANKL-induced group. Meanwhile, the results of immunofluorescence and immunohistochemistry showed that artesunate could dose-dependently reduce the expression of CCR3 in osteoclasts and joint tissues of the CIA rat model in vitro. This study indicated that artesunate regulated the CCR3 in the cytokine-cytokine receptor interaction signaling pathway in the treatment of bone destruction in RA and provided a new target gene for the treatment of bone destruction in RA.

Therapeutic Effect of IL-21 Blockage by Gene Therapy in Experimental Autoimmune Encephalomyelitis.

The pathogenic role of the interleukin 21 (IL-21) in different autoimmune diseases, such as multiple sclerosis (MS), has been extensively studied. However, its pleiotropic nature makes it a cytokine that may exhibit different activity depending on the immunological stage of the disease. In this study, we developed a gene therapy strategy to block the interaction between IL-21 and its receptor (IL-21R) by using adeno-associated vectors (AAV) encoding a new soluble cytokine receptor (sIL21R) protein. We tested this strategy in a murine model of experimental autoimmune encephalomyelitis (EAE), obtaining different clinical effects depending on the time at which the treatment was applied. Although the administration of the treatment during the development of the immune response was counterproductive, the preventive administration of the therapeutic vectors showed a protective effect by reducing the number of animals that developed the disease, as well as an improvement at the histopathological level and a modification of the immunological profile of the animals treated with the AAV8.sIL21R. The beneficial effect of the treatment was also observed when inducing the expression of the therapeutic molecule once the first neurological signs were established in a therapeutic approach with a doxycyline (Dox)-inducible expression system. All these clinical results highlight the pleiotropicity of this cytokine in the different clinical stages and its key role in the EAE immunopathogenesis.

A novel cytokine consisting of the p40 and EBI3 subunits suppresses experimental autoimmune arthritis via reciprocal regulation of Th17 and Treg cells.

OBJECTIVE: The interleukin (IL)-12 cytokine family is closely related to the development of T helper cells, which are responsible for autoimmune disease enhancement or suppression. IL-12 family members are generally heterodimers and share three α-subunits (p35, p19, and p28) and two ß-subunits (p40 and EBI3). However, a ß-sheet p40 homodimer has been shown to exist and antagonize IL-12 and IL-23 signaling 1. Therefore, we assumed the existence of a p40-EBI3 heterodimer in nature and sought to investigate its role in immune regulation. METHODS: The presence of the p40-EBI3 heterodimer was confirmed by ELISA, immunoprecipitation, and western blotting. A p40-EBI3 vector and p40-EBI3-Fc protein were synthesized to confirm the immunological role of this protein in mice with collagen-induced arthritis (CIA). The anti-inflammatory effects of p40-EBI3 were analyzed with regard to clinical, histological, and immune cell-regulating features in mice with CIA. RESULTS: Clinical arthritis scores and the expression levels of proinflammatory cytokines (e.g., IL-17, IL-1ß, IL-6, and TNF-α) were significantly attenuated in p40-EBI3-overexpressing and p40-EBI3-Fc-treated mice with CIA compared to vehicle-treated mice with CIA. Structural joint damage and vessel formation-related gene expression were also reduced by p40-EBI3 heterodimer treatment. In vitro, the p40-EBI3-Fc protein significantly suppressed the differentiation of Th17 cells and reciprocally induced CD4+CD25+Foxp3+ (regulatory T) cells. p40-EBI3 also inhibited osteoclast formation in a concentration-dependent manner. CONCLUSION: In this study, p40-EBI3 ameliorated proinflammatory conditions both in vivo and in vitro. We propose that p40-EBI3 is a novel anti-inflammatory cytokine involved in suppressing the immune response through the expansion of Treg cells and suppression of Th17 cells and osteoclastogenesis.

Biomimetic anti-inflammatory nano-capsule serves as a cytokine blocker and M2 polarization inducer for bone tissue repair.

Controlling of pro-inflammation induced by pro-inflammatory cytokines and anti-inflammatory response induced by M2 macrophages is important for osteogenesis in the process of bone tissue repair. Thus, we fabricated biomimetic anti-inflammatory nano-capsule (BANC) that can block cytokines and promote M2 macrophage polarization, presenting a positive role for bone tissue repair. The BANC is a biomimic nanosystem, coated with lipopolysaccharide-treated macrophage cell membranes with cytokine receptors enveloping gold nanocage (AuNC) as "cytokine blocker", and loaded with resolvin D1 inside into AuNC as "M2 polarization inducer" whose controlled-release could be triggered under near-infrared laser irradiation in sequence, and these chronological events were consistent with the healing process of bone tissue repair. Moreover, in vivo application of femoral bone defects revealed that the BANC composite boron-containing mesoporous bioactive glass scaffolds improved the final effects of bone tissue repair through preventing inflammatory response, promoting M2 polarization in sequence in accord with the in vitro investigation. Hence, cytokine neutralization and M2 macrophage polarization enables the BANC to enhance the bone tissue repair as a biomimetic anti-inflammation effector. Therefore, this study provides potential therapeutic strategies for trauma-mediated or inflammation-related bone defects based on a biomimetic nanomaterial with weakened pro-inflammatory and enhanced anti-inflammatory effects. STATEMENT OF SIGNIFICANCE: Cell membrane-mimic nanomaterials have been popular for blocking natural cell responses for some infection diseases, yet their role in biological process of bone repair is unknown. Here, we fabricated Biomimetic Anti-inflammatory Nano-Capsule (BANC), coated with cell membrane with cytokines receptors on the surface which could neutralize the pro-inflammatory cytokine receptor to block activated pro-inflammation, loaded with Resolvin D1 inside which could be controllably released by NIR irradiation to promote M2 macrophage polarization for the following bone formation during the process of bone repair. Administration of BANC as cytokines blocker and M2 polarization inducer to enhance the bone regeneration, thus presenting a promising potential for the treatment of bone repair and regeneration.

Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells.

Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7R-coexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer.Significance: The constitutively signaling C7R system developed here delivers potent IL7 stimulation to CAR T cells, increasing their persistence and antitumor activity against multiple preclinical tumor models, supporting its clinical development. Cancer Discov; 7(11); 1238-47. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1201.

Psoriasis, artritis psoriásica y enfermedad de Crohn: circuitos de citocinas y papel de la disbiosis / Cytokine Pathways and the Role of Dysbiosis in Psoriasis, Psoriatic Arthritis, and Crohn Disease

No disponible

Orbitopatía de Graves: una enfermedad poco conocida por el oftalmólogo. «El presente y el futuro está en los inhibidores de citoquinas. Cómo y cuándo utilizarlas» / Graves’ ophthalmopathy: A disease little-known by the ophthalmologist. The present and future is in cytokinase inhibitors. How and when to use them

No disponible

Avances en terapia farmacológica y fitoquímica de la adipogénesis / Advances in pharmacological and phytochemical adipogenesis therapy

La principal función de los adipocitos es el almacenamiento de lípidos cuando hay exceso de energía y la movilización de la misma cuando hay deficiencia. Una de las características de la obesidad es el aumento de la cantidad y el tamaño de los adipocitos, lo que implica la diferenciación de preadipocitos (PAD). El tejido adiposo (TA) tiene su origen en la etapa prenatal y puede seguir expandiéndose durante la vida adulta a partir de células precursoras, ya que los adipocitos maduros no pueden multiplicarse por división celular. El presente estudio proveerá información reciente de los eventos que se producen durante el origen y diferenciación de los PAD, así como los factores implicados en la regulación de la adipogénesis y los mecanismos que regulan las funciones fisiológicas del TA (AU)

The main function of the adipocyte is lipid storage when there is a positive energy balance and lipid release when there is and energy deficiency. One characteristic of obesity is an increase in the number and size of adipocytes, which implies pre adipocyte (PAD) differentiation. The adipose tissue (AT) has its origins in the prenatal stage and may continue to expand during adulthood from precursor cells since mature adipocytes cannot multiply by cell division. This study provide updates on the events that occur during the origin and differentiation of PAD, the factors involved in the regulation of adipogenesis and mechanisms that regulate physiological functions of AT (AU)

Esquistossomose mansônica humana: avaliação do receptor antagonista de IL-13 (IL-13Ra2) e da resposta imune celular / Human schistosomiasis: evaluation of receptor antagonist IL-13 (IL-13ra2) and cellular immune responses

Estudos indicam que citocinas Th1 (IL-2, TNF-alfa e IFN-gama) reduzem a fibrose na esquistossomose mansônica, enquanto que as Th2 (IL-4, IL-5, IL-6, IL-10 e IL-13) tem papel crítico na patogênese da doença. O desenvolvimento da resposta Th2 é dependente de IL-4, mas estudos revelaram a IL-13 como a mediadora da fibrose. Os mecanismos de controle da IL-13 estão ligados aos receptores desta citocina. O receptor IL-13Ra2, conhecida como receptor antagonista se liga com alta afinidade a IL-13, e estudos identificaram a sua participação na diminuição da fibrose e tamanho do granuloma. O principal objetivo desse projeto é avaliar o papel do IL-13Ra2 e da resposta imune celular nos diferentes graus de fibrose hepática e nas formas clínicas da esquistossomose mansônica humana. Os pacientes com diversas formas clínicas foram selecionados no Ambulatório de Gastroenterologia do HC- UFPE e avaliados através da ultrassonografia. As citocinas Th1 e Th2 foram dosadas através de citometria de fluxo e ELISA (IL-13 e IFN-gama), para a análise estatística foram utilizados testes de Mann-Whitney e Kruskal-Wallis e o teste de correlação de Spearman considerando um p 0,05 como significativo. Foi encontrado uma correlação negativa (p 0,05) entre o IL-13Ra2 e a IL-13, sugerindo um aumento da citocina no início da fibrose. Foi encontrada correlação inicialmente negativa nos pacientes sem fibrose e posteriormente positiva, nos pacientes com fibrose grave, entre IFN-gama e IL-13, salientando um novo mecanismo de regulação no processo de fibrose periportal na doença. Houve correlação positiva entre as citocinas do perfil Th1 e entre as citocinas do perfil Th2, sugerindo falta de supressão imunológica e presença de ambas às respostas, regulando a doença, com diferentes graus de fibrose periportal. Os resultados contribuirão para um melhor entendimento sobre os mecanismos imunes que controlam o processo de fibrogênese hepática em humanos e poderão ainda permitir um melhor entendimento da relação entre resposta imune celular e esquistossomose mansônica.

Allergen-specific immunotherapy: Update on immunological mechanisms

Immunotherapy selectively modulates the allergen-specific immune response. It involves the gradual administration of increasing amounts of allergen for the purpose of inducing protective immunological changes and it is the only curative approach for specific type I allergy (AU)

Endocarditis micótica en pacientes sin cardiopatías previas / Infective fungal endocarditis in patients with no previous cardiac disease

La endocarditis infecciosa es una grave y poco frecuente afección del endocardio. La etiología micótica representa menos del 10% de dichos casos. Cada vez son más frecuentes, como grupos de riesgo, los niños con tratamiento antibiótico endovenoso, alimentación parenteral y catéteres venosos centrales por tiempo prolongado, aún sin cardiopatías previas. Se revisaron retrospectivamente las historias clínicas de 6 niños con endocarditis por Cándida y se describen los factores predisponentes, la evolución clínica y la terapéutica empleada. Los antimicóticos empleados fueron anfotericin B, 5-fluorocitocina y fluconazol. Se realizó exéresis quirúrgica de las vegetaciones, 5 plastias valvulares tricuspídeas y una sustitución valvular mitral. Sobrevivieron todos los pacientes y uno necesitó nueva plastia valvular tricuspídea después de un año de operado. Con un seguimiento medio de 5 años, todos mantienen buena función valvular sin recidivas infecciosas. Se recomienda una combinación de tratamiento antimicótico sinérgico y prolongado con la intervención quirúrgica precoz(AU)

Infective endocarditis is a serious and uncommon condition affecting the endocardium. Less than 10% of these cases are of fungal origin. A growing number of individuals are at high risk, due to insertion of central venous catheters, total parenteral nutrition and prolonged exposure to broad-spectrum antibiotics, even without previous heart diseases. We retrospectively analysed the records of six children with Candida endocarditis, reviewing the comorbidities, clinical outcome, and treatment. The antifungal agents used were amphotericin B, 5-fluorocytosine and fluconazole. Patients underwent surgical excision of vegetation, five tricuspid valve repairs and one mitral valve replacement. There were no hospital deaths, and one child needed a new valvuloplasty one year later. The mean follow up was five years, and all have good valvular function without recurrent endocarditis. A combination of synergistic long-term antifungal treatment and early surgical intervention is recommended(AU)

Cytokine-like factor 1 gene expression is enriched in idiopathic pulmonary fibrosis and drives the accumulation of CD4+ T cells in murine lungs: evidence for an antifibrotic role in bleomycin injury.

Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease. To gain insight into the pathogenesis of IPF, we reanalyzed our previously published gene expression data profiling IPF lungs. Cytokine receptor-like factor 1 (CRLF1) was among the most highly up-regulated genes in IPF lungs, compared with normal controls. The protein product (CLF-1) and its partner, cardiotrophin-like cytokine (CLC), function as members of the interleukin 6 (IL-6) family of cytokines. Because of earlier work implicating IL-6 family members in IPF pathogenesis, we tested whether CLF-1 expression contributes to inflammation in experimental pulmonary fibrosis. In IPF, we detected CLF-1 expression in both type II alveolar epithelial cells and macrophages. We found that the receptor for CLF-1/CLC signaling, ciliary neurotrophic factor receptor (CNTFR), was expressed only in type II alveolar epithelial cells. Administration of CLF-1/CLC to both uninjured and bleomycin-injured mice led to the pulmonary accumulation of CD4(+) T cells. We also found that CLF-1/CLC administration increased inflammation but decreased pulmonary fibrosis. CLF-1/CLC leads to significantly enriched expression of T-cell-derived chemokines and cytokines, including the antifibrotic cytokine interferon-γ. We propose that, in IPF, CLF-1 is a selective stimulus of type II alveolar epithelial cells and may potentially drive an antifibrotic response by augmenting both T-helper-1-driven and T-regulatory-cell-driven inflammatory responses in the lung.

A soluble thymic stromal lymphopoietin (TSLP) antagonist, TSLPR-immunoglobulin, reduces the severity of allergic disease by regulating pulmonary dendritic cells.

Recent studies show that thymic stromal lymphopoietin (TSLP) plays a critical role in the upstream phase of the allergic cascade to induce T helper type 2 cell (Th2)-dominant allergic diseases. However, the effect of blocking TSLP signalling with the soluble TSLP receptor (TSLPR), TSLPR-immunoglobulin (Ig), on asthma development needs further investigation. Here, we examined the effects of TSLPR-Ig on asthmatic airway inflammation and dendritic cell (DC) function. TSLPR-Ig (comprising the extracellular domain of murine TSLPR and an IgG2a Fc tail) purified from transfected COS-7 cells reduced the expression of CD40, CD80 and CD86 on TSLP-activated DCs in vitro. We also investigated the mechanisms underlying TSLPR-Ig-mediated amelioration of allergic airway inflammation in a murine asthma model. When TSLP signalling was blocked by intratracheal administration of TSLPR-Ig prior to sensitization, allergen-specific serum IgE levels, airway tissue inflammation, inflammatory cell infiltration and Th2 cytokine levels in the bronchiolar lavage fluid (BALF) were reduced significantly. This was because of the TSLP-Ig-mediated down-regulation of co-stimulatory molecule expression on pulmonary DCs. We also transferred bone marrow-derived mature DCs (mDCs) into the airways of asthmatic mice. Intratracheal administration of TSLPR-Ig prior to the transfer of mDCs reduced eosinophilic airway inflammation and Th2 differentiation significantly. Collectively, these data suggest that local use of TSLPR-Ig prevents airway inflammation, at least in part, by regulating DC function, and that blocking TSLP signalling using TSLPR-Ig may be a novel strategy for the treatment of asthma bronchiale.

Immunomodulators in asthma therapy.

New developments in the field of allergy and immunology have yielded a variety of novel therapeutic approaches in recent years, and more agents are at the clinical trial stage. Among the therapeutic approaches discussed in this review are Toll-like receptor agonists, immunostimulatory oligodeoxynucleotides, orally and parenterally administered cytokine blockers, and specific cytokine receptor antagonists. Transcription factor modulators targeting syk kinase, peroxisome proliferator-activated receptor-gamma, and nuclear factor-kappaB are also being evaluated in the treatment of asthma. The anti-IgE monoclonal antibody omalizumab has established effectiveness in patients with allergic asthma, but the criteria for selecting patients who are most likely to benefit from it are less clear. This review summarizes data from human clinical trials with immunomodulators to discuss the rationale for their use, their efficacy, and adverse events associated with them.

Anti-cytokine therapeutics: history and update.

Anti-cytokine therapy has promoted a revolution in the treatment of several inflammatory disorders during the past 10 years. Despite their medical and commercial success, they exhibit several drawbacks: difficulties of production, excessive costs, and a few side-effects. A promising alternative to the passive infusion of monoclonal antibodies or soluble cytokine receptors is the use of the active anti-cytokine immune therapy (ACIT). Surprisingly, clinical studies suggested the interest of this approach during the late 1980's, even before the advent of anti-cytokine passive immunotherapy. In this review, we first explain the involvement of several cytokines in many common diseases involving cytokine overproduction, and identify key targets for anti-cytokine treatments. We then present an update on current advances in preclinical and clinical development of passive anti-cytokine therapeutic approaches. We further discuss progresses in the promising field of active anti-cytokine immunotherapy. Cytokine receptors biologics and small molecules developed using structure/function information, which also constitute important options for treating the cytokine-mediated diseases, are not discussed in this review.