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Activating Janus kinase (JAK) and signal transducer and activator of transcription (STAT) mutations have been discovered in many T-cell malignancies, including anaplastic lymphoma kinase (ALK)⁻ anaplastic large cell lymphomas (ALCLs). However, such mutations occur in a minority of patients. To investigate the clinical application of targeting JAK for ALK− ALCL, we treated ALK− cell lines of various histological origins with JAK inhibitors. Interestingly, most exogenous cytokine-independent cell lines responded to JAK inhibition regardless of JAK mutation status. JAK inhibitor sensitivity correlated with the STAT3 phosphorylation status of tumor cells. Using retroviral shRNA knockdown, we have demonstrated that these JAK inhibitor-sensitive cells are dependent on both JAK1 and STAT3 for survival. JAK1 and STAT3 gain-of-function mutations were found in some, but not all, JAK inhibitor-sensitive cells. Moreover, the mutations alone cannot explain the JAK1/STAT3 dependency, given that wild-type JAK1 or STAT3 was sufficient to promote cell survival in the cells that had either JAK1or STAT3 mutations. To investigate whether other mechanisms were involved, we knocked down upstream receptors GP130 or IL-2Rγ. Knockdown of GP130 or IL-2Rγ induced cell death in selected JAK inhibitor-sensitive cells. High expression levels of cytokines, including IL-6, were demonstrated in cell lines as well as in primary ALK− ALCL tumors. Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft ALK− ALCL model. Our data suggest that cytokine receptor signaling is required for tumor cell survival in diverse forms of ALK− ALCL, even in the presence of JAK1/STAT3 mutations. Therefore, JAK inhibitor therapy might benefit patients with ALK− ALCL who are phosphorylated STAT3⁺.

Abstract Rationale The drug product TPI ASM8 contains two modified phosphorothioate antisense oligonucleotides designed to inhibit allergic inflammation by down-regulating human CCR3 and the common beta chain (βc) of IL-3, IL-5, and granulocyte-macrophage colony–stimulating factor receptors. Objectives This study examined the effects of inhaled TPI ASM8 on sputum cellular influx, CCR3 and βc mRNA and protein levels, and the airway physiologic response after inhaled allergen. Methods Seventeen subjects with mild atopic asthma were randomized in a crossover study to inhale 1,500 μg TPI ASM8 or placebo by nebulizer, once daily for 4 days. On Day 3, subjects underwent allergen inhalation challenge. Sputum samples were collected before and after allergen. CCR3 and βc protein levels were measured by flow cytometry, mRNA was measured using real-time quantitative polymerase chain reaction, and the FEV1 was measured over 7 hours after challenge. Measurements and Main Results Compared with placebo, TPI ASM8 inhibited sputum eosinophil influx by 46% (P = 0.02) and blunted the increase in total cells (63%) after allergen challenge. TPI ASM8 significantly reduced the early asthmatic response (P = 0.04) with a trend for the late asthmatic response (P = 0.08). The allergen-induced (Day 2 to Day 3) levels of βc mRNA and CCR3 mRNA in sputum-derived cells were inhibited by TPI ASM8 (P = 0.039 and P = 0.054, respectively), with no significant effects on the cell surface protein expression of CCR3 and βc (P > 0.05). No serious adverse events were reported. Conclusions TPI ASM8 attenuates the allergen-induced increase in target gene mRNA and airway responses in subjects with mild asthma. Clinical trial registered with www.clinicaltrials.gov (NCT00264966).

Background: Passiflora setacea (PS) is a passionfruit variety of the Brazilian savannah and is a rich source of plant food bioactives with potential anti-inflammatory activity. This study aimed to investigate the effect of an acute intake of PS juice upon inflammation, metabolic parameters, and gene expression on circulating immune cells in humans. Methods: Overweight male volunteers (n = 12) were enrolled in two double-blind placebo-controlled studies. Blood samples were collected from fasting volunteers 3 h after the consumption of 250 mL of PS juice or placebo (PB). Metabolic parameters (insulin, glucose, total cholesterol, high-density lipoprotein (LDL), high-density lipoprotein (HDL), and total triglycerides) and circulating cytokines were evaluated (study 1). Peripheral blood mononuclear cell (PBMC) from the same subjects were isolated and RNA was extracted for transcriptomic analyses using microarrays (study 2). Results: Insulin and homeostatic model assessment for insulin resistance (HOMA-IR) levels decreased statistically after the PS juice intake, whereas HDL level increased significantly. Interleukin (IL)-17A level increased after placebo consumption, whereas its level remained unchanged after PS juice consumption. Nutrigenomic analyses revealed 1327 differentially expressed genes after PS consumption, with modulated genes involved in processes such as inflammation, cell adhesion, or cytokine–cytokine receptor. Conclusion: Taken together, these clinical results support the hypothesis that PS consumption may help the prevention of cardiometabolic diseases.

HIV-1 and related viruses require co-receptors, in addition to CD4, to infect target cells. The chemokine receptor CCR-5 (ref. 1) was recently demonstrated to be a co-receptor for macrophage-tropic (M-tropic) HIV-1 strains 2–6 , and the orphan 7 receptor LESTR (also called fusin) allows infection by strains adapted for growth in transformed T-cell lines (T-tropic strains). Here we show that a mutant allele of CCR-5 is present at a high frequency in caucasian populations (allele frequency, 0.092), but is absent in black populations from Western and Central Africa and Japanese populations. A 32-base-pair deletion within the coding region results in a frame shift, and generates a non-functional receptor that does not support membrane fusion or infection by macrophage- and dual-tropic HIV-1 strains. In a cohort of HIV-1-infected caucasian subjects, no individual homozygous for the mutation was found, and the frequency of heterozygotes was 35% lower than in the general population. White blood cells from an individual homozygous for the null allele were found to be highly resistant to infection by M-tropic HIV-1 viruses, confirming that CCR-5 is the major co-receptor for primary HIV-1 strains. The lower frequency of heterozygotes in seropositive patients may indicate partial resistance.

Genetic variants in IL6ST encoding the shared cytokine receptor for the IL-6 cytokine family GP130 have been associated with a diverse number of clinical phenotypes and disorders. We provide a molecular classification for 59 reported rare IL6ST pathogenic or likely pathogenic variants and additional polymorphisms. Based on loss- or gain-of-function, cytokine selectivity, mono- and biallelic associations, and variable cellular mosaicism, we grade six classes of IL6ST variants and explore the potential for additional variants. We classify variants according to the American College of Medical Genetics and Genomics criteria. Loss-of-function variants with (i) biallelic complete loss of GP130 function that presents with extended Stüve-Wiedemann Syndrome; (ii) autosomal recessive hyper-IgE syndrome (HIES) caused by biallelic; and (iii) autosomal dominant HIES caused by monoallelic IL6ST variants both causing selective IL-6 and IL-11 cytokine loss-of-function defects; (iv) a biallelic cytokine-specific variant that exclusively impairs IL-11 signaling, associated with craniosynostosis and tooth abnormalities; (v) somatic monoallelic mosaic constitutively active gain-of-function variants in hepatocytes that present with inflammatory hepatocellular adenoma; and (vi) mosaic constitutively active gain-of-function variants in hematopoietic and non-hematopoietic cells that are associated with an immune dysregulation syndrome. In addition to Mendelian IL6ST coding variants, there are common non-coding cis-acting variants that modify gene expression, which are associated with an increased risk of complex immune-mediated disorders and trans-acting variants that affect GP130 protein function. Our taxonomy highlights IL6ST as a gene with particularly strong functional and phenotypic diversity due to the combinatorial biology of the IL-6 cytokine family and predicts additional genotype-phenotype associations.

Inflammatory bowel diseases (IBDs) are chronic inflammatory diseases of the gastrointestinal tract, which are clinically present as 1 of the 2 disorders, Crohn's disease (CD) or ulcerative colitis (UC) (Rogler 2004). The immune dysregulation in the intestine plays a critical role in the pathogenesis of IBD, involving a wide range of molecules, including cytokines. The aim of this work was to study the involvement of T-helper 17 (Th17) subset in the bowel disease pathogenesis by the nitric oxide (NO) pathway in Algerian patients with IBD. We investigated the correlation between the proinflammatory cytokines [(interleukin (IL)-17, IL-23, and IL-6] and NO production in 2 groups of patients. We analyzed the expression of messenger RNAs (mRNAs) encoding Th17 cytokines, cytokine receptors, and NO synthase 2 (NOS2) in plasma of the patients. In the same way, the expression of p-signal transducer and activator of transcription 3 (STAT3) and NOS2 was measured by immunofluorescence and immunohistochemistry. We also studied NO modulation by proinflammatory cytokines (IL-17A, IL-6, tumor necrosis factor α, or IL-1β) in the presence or absence of all-trans retinoic acid (At RA) in peripheral blood mononuclear cells (PBMCs), monocytes, and in colonic mucosa cultures. Analysis of cytokines, cytokine receptors, and NOS2 transcripts revealed that the levels of mRNA transcripts of the indicated genes are elevated in all IBD groups. Our study shows a significant positive correlation between the NO and IL-17A, IL-23, and IL-6 levels in plasma of the patients with IBD. Interestingly, the correlation is significantly higher in patients with active CD. Our study shows that both p-STAT3 and inducible NOS expression was upregulated in PBMCs and colonic mucosa, especially in patients with active CD. At RA downregulates NO production in the presence of proinflammatory cytokines for the 2 groups of patients. Collectively, our study indicates that the IL-23/IL-17A axis plays a pivotal role in IBD pathogenesis through the NO pathway.

BackgroundCytokines are key regulators of measles vaccine humoral and cellular immunity. Single-nucleotide polymorphisms (SNPs) that are associated with differences in cytokine levels should also influence measles vaccine–induced immunity MethodsWe genotyped 118 measles-mumps-rubella–vaccinated subjects for SNPs from 6 cytokine genes (interleukin [IL]–2, IL-4, IL-10, IL-12A, IL-12B, and interferon [IFN]–γ) and their receptors (IL-2RA, IL-2RB, IL-4RA, IL-10RA, IL-10RB, IL-12RB1, IL-12RB2, and IFN-γR). Associations of SNPs with measles-specific antibodies, lymphoproliferation, and secreted cytokines were determined using χ2 tests and analyses of covariance ResultsWe found significant associations (P<.05) between SNPs in the IL-2, IL-10, and IL-12RB genes and measles vaccine–induced immunity. The IVS1-100G (rs2069762) and the Ex2-34G (rs2069763) SNPs within the IL-2 gene were associated with high antibody and high lymphoproliferative responses, whereas SNPs within the IL-10 and IL-12R genes were associated with low antibody and lymphoproliferative responses to measles. SNPs within the IL-4RA and IL-12B genes varied significantly (P<.05) across immune response measures. Significant associations were also found between SNPs and secreted cytokine levels ConclusionsSpecific SNPs in the cytokine and cytokine receptor genes are significantly associated with variations in measures of the immune response to measles vaccination. These results need to be further validated in a larger cohort

The IL-6 cytokine family signals through the common signal transduction molecule gp130 combined with a cytokine-specific receptor. Gp130 signaling on CD4 T cells is vital in controlling chronic infection of mice with lymphocytic choriomeningitis virus clone 13 (LCMV Cl13), but the precise role of individual members of the IL-6 cytokine family is not fully understood. Transcriptional analysis highlighted the importance of gp130 signaling in promoting key processes in CD4 T cells after LCMV Cl13 infection, particularly genes associated with T follicular helper (Tfh) cell differentiation and IL-21 production. Further, Il27r −/− Il6ra −/− mice failed to generate antibody or CD8 T-cell immunity and to control LCMV Cl13. Transcriptomics and phenotypic analyses of Il27r −/− Il6ra −/− Tfh cells revealed that IL-6R and IL-27R signaling was required to activate key pathways within CD4 T cells. IL-6 and IL-27 signaling has distinct and overlapping roles, with IL-6 regulating Tfh differentiation, IL-27 regulating CD4 T cell survival, and both redundantly promoting IL-21.

Interferons (IFNs) are critical soluble factors in the immune system and are composed of three types, (I, II and III) that utilize different receptor complexes IFN-αR1/IFN-αR2, IFN-γR1/IFN-γR2, and IFN-λR1/IL-10R2, respectively. Here we identify IFN-υ from the genomic sequences of vertebrates. The members of class II cytokine receptors, IFN-υR1 and IL-10R2, are identified as the receptor complex of IFN-υ, and are associated with IFN-υ stimulated gene expression and antiviral activity in zebrafish ( Danio rerio ) and African clawed frog ( Xenopus laevis ). IFN-υ and IFN-υR1 are separately located at unique and highly conserved loci, being distinct from all other three-type IFNs. IFN-υ and IFN-υR1 are phylogenetically clustered with class II cytokines and class II cytokine receptors, respectively. Therefore, the finding of this IFN ligand-receptor system may be considered as a type IV IFN, in addition to the currently recognized three types of IFNs in vertebrates. Interferons are critical soluble components of the inflammatory process and are composed of three types with associated receptor complexes. Here the authors identify and characterise the type IV interferon, IFN-υ, and identify its associated receptors, denote functionality during in vivo infection and ascertain its genomic localisation.

Animals have evolved circadian rhythms to adapt to the 24-h day-night cycle. Circadian rhythms are controlled by molecular clocks in the brain and periphery, which is driven by clock genes. The circadian rhythm is propagated from the brain to the periphery by nerves and hormones. Glucocorticoids (GCs) are a class of steroid hormones produced by the adrenal cortex under the control of the circadian rhythm and the stress. GCs have both positive and negative effects on the immune system. Indeed, they are well known for their strong anti-inflammatory and immunosuppressive effects. Endogenous GCs inhibit the expression of inflammatory cytokines and chemokines at the active phase of mice, regulating the circadian rhythm of tissue inflammation. In addition, GCs induce the rhythmic expression of IL-7R and CXCR4 on T cells, which supports T cell maintenance and homing to lymphoid tissues. Clock genes and adrenergic neural activity control the T cell migration and immune response. Taken together, circadian factors shape the diurnal oscillation of innate and adaptive immunity. Among them, GCs participate in the circadian rhythm of innate and adaptive immunity by positive and negative effects.