Interleukin-1 Receptor-Like 2: One Receptor, Three Agonists, and Many Implications.

The interleukin (IL)-1 superfamily of cytokines comprises 11 pro- and anti-inflammatory cytokines, which play essential roles during the immune response. Several pathogenic pathways are initiated by IL-1RL2 (interleukin 1 receptor-like 2) signaling, also known as IL-36R, in the skin, lungs, and gut. IL-36 cytokines promote the secretion of proinflammatory cytokines and chemokines, upregulation of antimicrobial peptides, proliferation mediators, and adhesion molecules on endothelial cells. In addition, the IL-36-IL-1RL2 axis has an essential role against viral infections, including a potential role in COVID-19 pathology. The evidence presented in this review highlights the importance of the axis IL-36-IL-1RL2 in the development of several inflammation-related diseases and the healing process. It suggests that IL-1RL2 ligands have specific roles depending on the tissue or cell source. However, there is still much to discover about this cytokine family, their functions in other organs, and how they accomplish a dual effect in inflammation and healing.

Toxoplasma gondii-Induced Neutrophil Extracellular Traps Amplify the Innate and Adaptive Response.

Toxoplasmosis affects one-third of the human population worldwide. Humans are accidental hosts and are infected after consumption of undercooked meat and water contaminated with Toxoplasma gondii cysts and oocysts, respectively. Neutrophils have been shown to participate in the control of T. gondii infection in mice through a variety of effector mechanisms, such as reactive oxygen species (ROS) and neutrophil extracellular trap (NET) formation. However, few studies have demonstrated the role of neutrophils in individuals naturally infected with T. gondii. In the current study, we evaluated the activation status of neutrophils in individuals with acute or chronic toxoplasmosis and determined the role of T. gondii-induced NET formation in the amplification of the innate and adaptive immune responses. We observed that neutrophils are highly activated during acute infection through increased expression of CD66b. Moreover, neutrophils from healthy donors (HDs) cocultured with tachyzoites produced ROS and formed NETs, with the latter being dependent on glycolysis, succinate dehydrogenase, gasdermin D, and neutrophil elastase. Furthermore, we observed elevated levels of the chemokines (CXC motif) CXCL8 and (CC motif) CCL4 ligands in plasma from patients with acute toxoplasmosis and production by neutrophils from HDs exposed to T. gondii. Finally, we showed that T. gondii-induced NETs activate neutrophils and promote the recruitment of autologous CD4+ T cells and the production of interferon gamma (IFN-γ), tumor necrosis factor (TNF), interleukin 6 (IL-6), IL-17, and IL-10 by peripheral blood mononuclear cells. In conclusion, we demonstrated that T. gondii activates neutrophils and promotes the release of NETs, which amplify human innate and adaptive immune responses. IMPORTANCE Approximately one-third of the human population is estimated to be chronically infected with the obligate intracellular parasite Toxoplasma gondii. Humans are accidental hosts that are infected with T. gondii after consumption of undercooked meat or contaminated water. Neutrophils have been shown to control T. gondii growth by different mechanisms, including neutrophil extracellular traps (NETs). In the current study, we observed that neutrophils are highly activated during acute toxoplasmosis. We also determined that T. gondii-induced NETs are dependent on the energetic profile of neutrophils as well as the production of ROS and gasdermin D (GSDMD) cleavage. In addition, we showed that T. gondii-induced NETs activate neutrophils, promote the recruitment of autologous CD4+ T cells, and induce the production of cytokines by peripheral blood mononuclear cells, amplifying the innate and adaptive immune responses.

AIDS incidence and survival in a hospital-based cohort of HIV-positive patients from São Paulo, Brazil: The role of IFN-λ4 polymorphisms.

Few studies have reported the prognosis of human immunodeficiency virus (HIV)-positive patients followed for a long time in Brazil, particularly those including pre and post-HAART eras. The polymorphisms of interferon (IFN)-λ4 have been postulated as possibly associated with the pathogenesis of HIV infection. The aim of this study was to describe the incidence and mortality from a cohort of HIV-positive patients as well as whether IFN-λ4 gene polymorphisms (SNP rs8099917 and SNP rs12979860) were associated with HIV/acquired immune deficiency syndrome (AIDS) progression. We followed 402 patients for up to 30 years; 347 of them began follow-up asymptomatic, without any AIDS-defining opportunistic disease and/or a lymphocytes T CD4+ count of 350 cells/mm3 or lower. We determined the probability of the asymptomatic subjects to remain AIDS-free, and the risk of death for those entering the study already with an AIDS diagnosis, as well as for subjects developing AIDS during follow-up. We compared the prognosis of patients with two different polymorphisms for the genes encoding for IFN-λ4, variants rs8099917 and rs12979860. The follow-up time of the 347 asymptomatic-at-entry subjects was 3687 person-years. IFN-λ4 rs8099917 polymorphisms were not associated with AIDS progression, but IFN-λ4 rs12979860 wild type genotype (CC) was associated with higher mortality compared to CT and TT, with an increased probability of death from AIDS (P = .01). In conclusion, genetic variations in IFN-λ4 on rs12979860 polymorphisms in HIV-infected patients may drive mortality risk.

Identification of antigenic epitopes of thyroperoxidase, thyroglobulin and interleukin-24. Exploration of cross-reactivity with environmental allergens and possible role in urticaria and hypothyroidism.

BACKGROUND: Human proteins such as interleukin-24 (IL24), thyroperoxidase (TPO) and thyroglobulin (Tg) are targets of IgE or IgG autoantibodies. Why these proteins are recognized by autoantibodies in some patients with chronic spontaneous urticaria (CSU) or hypothyroidism is unknown. OBJECTIVE: Through in silico analysis, identify antigen patches of TPO, Tg and IL24 and compare the sequences of these human proteins with some prevalent allergens. METHODS: The amino acids sequences of IL24, thyroperoxidase and thyroglobulin were compared between them and with 22 environmental allergens. Phylogenetic studies and multiple pairing were carried out to explore the degree of protein identity and cover. The proteins without 3D structure reported in the database, were modeled by homology with "Swiss Modeller" and compared through PYMOL. Residues conserved and accessible to the solvent (rASA> 0.25) were located in the 3D model to identify possible areas of cross-reactivity and antigen binding. RESULTS: We build a 3D model of the TPO and thyroglobulin protein base on proteins closely related. Five epitopes for TPO, six for IL24 and six for thyroglobulin were predicted. The amino acid sequences of allergens from different sources (Dermatophagoides pteronyssinus, Blomia tropicalis, Betula verrucosa, Cynodon dactylon, Aspergillus fumigatus, Canis domesticus, Felis domesticus) were compared with human TPO, Tg and IL24. The cover and alignments between allergens and human proteins were low. CONCLUSION: We identify possible linear and conformational epitopes of TPO, Tg and IL24 that could be the target of IgE or IgG binding in patients with urticaria or hypothyroidism; These epitopes do not appear to be present among common environmental allergens, suggesting that autoreactivity to these human proteins are not by cross-reactivity.

The IFNL4 Gene Is a Noncanonical Interferon Gene with a Unique but Evolutionarily Conserved Regulation.

Interferon lambda 4 (IFN-λ4) is a recently identified enigmatic member of the interferon (IFN) lambda family. Genetic data suggest that the IFNL4 gene acts in a proviral and anti-inflammatory manner in patients. However, the protein is indistinguishable in vitro from the other members of the interferon lambda family. We have investigated the gene regulation of IFNL4 in detail and found that it differs radically from that of canonical antiviral interferons. Being induced by viral infection is a defining characteristic of interferons, but viral infection or overexpression of members of the interferon regulatory factor (IRF) family of transcription factors only leads to a minute induction of IFNL4 This behavior is evolutionarily conserved and can be reversed by inserting a functional IRF3 binding site into the IFNL4 promoter. Thus, the regulation of the IFNL4 gene is radically different and might explain some of the atypical phenotypes associated with the IFNL4 gene in humans.IMPORTANCE Recent genetic evidence has highlighted how the IFNL4 gene acts in a counterintuitive manner, as patients with a nonfunctional IFNL4 gene exhibit increased clearance of hepatitis C virus (HCV) but also increased liver inflammation. This suggests that the IFNL4 gene acts in a proviral and anti-inflammatory manner. These surprising but quite clear genetic data have prompted an extensive examination of the basic characteristics of the IFNL4 gene and its gene product, interferon lambda 4 (IFN-λ4). We have investigated the expression of the IFNL4 gene and found it to be poorly induced by viral infections. A thorough investigation of the IFNL4 promoter revealed a highly conserved and functional promoter, but also one that lacks the defining characteristic of interferons (IFNs), i.e., the ability to be effectively induced by viral infections. We suggest that the unique function of the IFNL4 gene is related to its noncanonical transcriptional regulation.

Increased TSLP, IL-33, IL-25, IL-19, IL 21 and amphiregulin (AREG) levels in chronic rhinosinusitis with nasal polyp.

OBJECTIVE: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease. The surrogate indicating biomarkers in patients with CRSwNP need further evaluation. The aim of this study was to investigate the association of thymic stromal lymphopoietin (TSLP) and amphiregulin (AREG) cytokines in patients with CRSwNP. METHODS: Sinonasal tissue samples were collected from 33 patients with CRSwNP and 29 controls. Levels of AREG, IL-19, IL-21, IL-25, IL-33 and TSLP in nasal polyp and control sinonasal tissues were determined following the enzyme-linked immunosorbent assay method. RESULTS: We found that AREG, IL-19, IL-21, IL-25, IL-33 and TSLP levels were significantly higher in the CRSwNP group compared to the control group (p < 0.000; p < 0.000; p < 0.000; p < 0.000; p < 0.003; p < 0.021, respectively). CONCLUSIONS: Our findings indicated that AREG, IL-19, IL-21, IL-25, IL-33 and TSLP were significantly increased in tissue samples of CRSwNP patients and may be considered as molecular indicators and targets for therapeutic developments for patients with CRSwNP.

Functional characterization of interleukin (IL)-22 and its inhibitor, IL-22 binding protein (IL-22BP) in Mandarin fish, Siniperca chuatsi.

As an important immune regulatory molecule, interleukin (IL)-22 has been reported in several species of fish, but its soluble receptor, IL-22 binding protein (IL-22BP), discovered as a natural antagonist of IL-22 in mammals, has not been functionally characterized in fish to date. In the present study, IL-22 and IL-22BP genes were cloned in mandarin fish Siniperca chuatsi. They all exhibited a high basal expression level in mucosa-enriched tissues, implying their possible roles in mucosal immunity. The IL-22 was found to show a potent response to LPS stimulation, acting as an inducer of antimicrobial peptide (AMP) genes, such as hepcidin and Liver-expressed antimicrobial peptide-2 (LEAP-2) in intestinal cells. IL-22BP, via co-incubation with IL-22, inhibited completely the induction of downstream genes by IL-22. Through a yeast two-hybrid assay, the interaction between IL-22BP and IL-22 was confirmed, which may account for the inhibitory effect of IL-22BP. Moreover, two hot spot residues for IL-22 binding, as reported in mammalian IL-22BP, were found to be conserved both in sequence location and function in mandarin fish IL-22BP, indicating that the interaction mode between IL-22 and IL-22BP may be also conserved in fish and mammals. In conclusion, the mandarin fish IL-22 and IL-22BP are conserved in their interaction and function with their mammalian orthologues, and these findings provide basis for future research on IL-22-IL-22BP axis in fish immunity.

The Effects of Endurance Exercise and Diet on Atherosclerosis in Young and Aged ApoE-/- and Wild-Type Mice.

BACKGROUND: Atherosclerosis is the leading cause of death worldwide. The disease development is by and large driven by old age and lifestyle factors, such as diet, physical activity, and smoking. In the present study, we have investigated the effect of exercise and diet on the development of atherosclerosis in young and aged mice. OBJECTIVE: This study aimed at comparing multiple age-dependent factors that may influence atherosclerosis in a transgenic mouse model. METHODS: Young (14 weeks) and aged (49-52 weeks) C57BL/6 wild-type (WT) and atherosclerosis-prone ApoE-/- mice were subjected to physical endurance exercise on a treadmill, with or without a high-fat diet. Five weeks later, the frequencies of regulatory T cells (TREGs) in lymph nodes were assessed by flow cytometry, plasmatic cytokines (interleukin [IL]-1ß, IL-6, IL-10, IL-17, interferon-γ, tumor necrosis factor-α, and transforming growth factor [TGF]-ß1) levels were determined by Luminex assay. Lipids (cholesterol and triglycerides) and anti-heat shock protein 60 (HSP60) autoantibodies were measured by ELISA. Aortic lesion sizes were assessed by en face imaging. Microarray analysis and qPCR of skeletal muscle gene expression were also performed. RESULTS: Exercise leads to a reduction of aortic lesions in young ApoE-/- and aged WT mice independent of diet. In most groups, this reduction was followed by an increased proportion of TREGs and TGF-ß1 levels. Moreover, gene expression analysis showed that exercise seems to affect the AMPK signaling pathway. In particular, PGC-1α1 mRNA was induced in aged WT mice, whereas it was reduced in young ApoE-/- mice. In addition, GSEA analysis showed a marked reduction in the insulin signaling pathway in aged ApoE-/- mice. CONCLUSION: Practicing endurance exercise seems to be enough for reducing early aortic lesion formation, independent of diet. However, this was only true in mice with smaller aortic lesions, since mice with large, advanced, complicated atherosclerotic plaques did not show any reduction in lesion size with exercise training.

The plasma levels of 12 cytokines and growth factors in patients with gastric cancer.

To assess the association of plasma cytokines and growth factor levels with clinical characteristics and inflammatory indices in patients with gastric cancer.Plasma samples derived from 99 gastric cancer patients were used for analysis. Levels of interferon (IFN)-γ, tumor growth factor (TGF)-ß1, tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, and vascular endothelial growth factor (VEGF) were measured by Luminex suspension array technology. The association between cytokine/growth factor levels and demographic/clinical characteristics was assessed. Correlation between cytokines and growth factor levels was assessed by Pearson's correlation analysis.Male patients had significant higher levels of plasma TNF-α, IL-12p70, IL-4, IL-10, and VEGF as compared with those in women (P < .05). Plasma levels of TNF-α in older patients with gastric cancer (≥60 years) were higher than those in young patients (P < .05). Elevated plasma levels of IL-8 and IL-10 were identified as risk factors for increased tumor size (diameter ≥5 cm). Higher plasma levels of TGF-ß1 were associated with increased risk of vascular or nerve invasion and advanced tumor stage. The levels of systemic inflammatory markers, including white blood cell counts, neutrophil/lymphocyte proportion, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), C-reactive protein and modified Glasgow prognostic score (mGPS) were closely associated with a series of plasma cytokines. A prominent correlation was observed between the plasma IL-12p70 and IFN-γ levels (r = 0.729, P < .01).Our findings suggest that plasma cytokines and growth factor levels may help predict the development and progression of gastric cancer. Our findings need to be validated by larger studies.

Modulation of Th1/Tc1 and Th17/Tc17 responses in pulmonary tuberculosis by IL-20 subfamily of cytokines.

Although IL-10 is known to be an important cytokine in the immune response to TB, very little is known about the role of IL-20 subfamily of cytokines in the host response to TB. To identify the role of CD4+ T and CD8+ T cells producing IL-20 subfamily of cytokines in human TB, we enumerated the frequencies of IL-10, IL-19 and IL-24 expressing CD4+ and CD8+ T cells following Mtb-specific antigen stimulation of cells from individuals with pulmonary TB (PTB) and latent TB (LTB). We first demonstrated that Mtb-specific antigen induce an expansion of CD4+ and CD8+ T cells expressing IL-10, IL-19 and IL-24 in PTB and LTB individuals, with frequencies being significantly higher in PTB. Next, we demonstrated that IL-10, IL-19 and IL-24 play an important role in the regulation of CD4+ and CD8+ T cells expressing Th1/Tc1 and Th17/Tc17 cytokines in PTB but not LTB individuals. Thus, active PTB is characterized by an IL-10, IL-19 and IL-24 mediated down modulation of Th1/Tc1 and/or Th17/Tc17 cytokines in CD4+ and CD8+ T cell subsets. This suggests that the IL-20 subfamily of cytokines, similar to IL-10 might play a potentially crucial role in the modulation of T cell responses in active TB disease.

Proinflammatory biomarkers' level and functional genetic polymorphisms in periprosthetic joint infection.

OBJECTIVE: The aims of this study were 1) to identify the level of inflammatory biomarkers interleukin (IL)-1α, IL-1ß, IL-6, IL-8, IL-17, C-reactive protein (CRP), granulocyte colony-stimulating factor (GCSF), ferritin, and tumor necrosis factor (TNF)-α in serum and synovial fluid samples of patients who underwent revision arthroplasty surgery; 2) to establish the relationship between serum and synovial fluid levels; 3) to determine if any of the 11 genetic polymorphisms of TNFα, IL-1, IL-6, IL-8, IL-17, and GCSF on the encoding genes was associated with periprosthetic joint infection (PJI). METHODS: Synovial fluid and serum was collected from 88 patients who underwent revision arthroplasty surgery. The Musculoskeletal Infection Society definition was used to classify these patients into 2 groups: 36 PJIs and 52 aseptic failures. Synovial fluid and serum samples were tested for 9 biomarkers using a micro enzyme-linked immunosorbent assay. Genetic polymorphisms were evaluated with polymerase chain reaction and restriction endonuclease analysis. RESULTS: Synovial fluid-derived IL-1α, IL-1ß, IL-8, IL-17, CRP, GCSF, TNFα, and serum-derived IL-6, IL-17, ferritin, CRP were found suitable to classify PJI and aseptic failure. In addition, IL-17 and CRP levels demonstrated a positive correlation between synovial fluid and serum. TNFα-238, IL6-174, GCSF3R, and IL1 RN-VNTR genetic polymorphisms occurred more frequently in individuals with septic failure. CONCLUSION: Significant differences between the two groups were observed in the functional polymorphisms of the genes encoding the cytokines investigated. These differences could be interpreted as indicating that there is an association between PJI and genetic polymorphisms. LEVEL OF EVIDENCE: Level III, diagnostic study.

IL-36 cytokines are increased in acne and hidradenitis suppurativa.

Interleukin (IL)-36 cytokines are new members of the IL-1 family, which include pro-inflammatory factors, IL-36α, IL-36ß and IL-36γ, and a natural receptor antagonist IL-36Ra. Over recent years, much has been learned on their important functions in the regulation of immune response and, especially, on their role in many inflammatory skin diseases. However, to date, no data have been reported on their possible involvement in acne and hidradenitis suppurativa (HS). Here, we have shown that IL-36α, IL-36ß, and IL-36γ are increased in lesional skin of acne and HS, highlighting their possible pathogenetic contribution to these two skin conditions. In contrast, IL-36Ra (the anti-inflammatory member of IL-36 sub-family) was increased just in psoriasis, suggesting that an imbalance in IL-36/IL36Ra functions could play a role in the phenotype of skin damage. One of the consequences of this imbalance may be the increased induction of IL-8 that we found higher in acne, HS, and ACD respect to psoriasis.

Analytically Sensitive Protein Detection in Microtiter Plates by Proximity Ligation with Rolling Circle Amplification.

BACKGROUND: Detecting proteins at low concentrations in plasma is crucial for early diagnosis. Current techniques in clinical routine, such as sandwich ELISA, provide sensitive protein detection because of a dependence on target recognition by pairs of antibodies, but detection of still lower protein concentrations is often called for. Proximity ligation assay with rolling circle amplification (PLARCA) is a modified proximity ligation assay (PLA) for analytically specific and sensitive protein detection via binding of target proteins by 3 antibodies, and signal amplification via rolling circle amplification (RCA) in microtiter wells, easily adapted to instrumentation in use in hospitals. METHODS: Proteins captured by immobilized antibodies were detected using a pair of oligonucleotide-conjugated antibodies. Upon target recognition these PLA probes guided oligonucleotide ligation, followed by amplification via RCA of circular DNA strands that formed in the reaction. The RCA products were detected by horseradish peroxidase-labeled oligonucleotides to generate colorimetric reaction products with readout in an absorbance microplate reader. RESULTS: We compared detection of interleukin (IL)-4, IL-6, IL-8, p53, and growth differentiation factor 15 (GDF-15) by PLARCA and conventional sandwich ELISA or immuno-RCA. PLARCA detected lower concentrations of proteins and exhibited a broader dynamic range compared to ELISA and iRCA using the same antibodies. IL-4 and IL-6 were detected in clinical samples at femtomolar concentrations, considerably lower than for ELISA. CONCLUSIONS: PLARCA offers detection of lower protein levels and increased dynamic ranges compared to ELISA. The PLARCA procedure may be adapted to routine instrumentation available in hospitals and research laboratories.

A review on interleukins: The key manipulators in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease associated with weakening of bones and joint pain. It primarily involves autoimmunity, matrix destruction, osteoclastogenesis, inflammation, and angiogenesis. Numerous cellular and humoral components of the immune system are involved in the etiology of diseases; however, the cardinal part is played by the inter-cellular signaling messengers called cytokines. Interleukins is a vaguely defined sub-class of cytokines that are abundantly found in the RA patients. The multifariousness and diversity in the function of the interleukins make them very likely to be associated with the pathogenesis in multiple ways. Nonetheless, the variety in opinions of researchers globally has led to contentious inferences. Ergo, in this review we have amalgamated the views of researchers from the past two decades till date to provide a comprehensive report about the role of interleukins in rheumatoid arthritis.

Association between interleukin-22 genetic polymorphisms and bladder cancer risk.

OBJECTIVE: The cytokine interleukin-22 (IL-22), which is produced by T cells and natural killer cells, is associated with tumorigenesis and tumor progression in cancers. However, the role of IL-22 in bladder cancer has not been investigated. MATERIALS AND METHODS: A prospective hospital-based case-control study comprising 210 patients with pathologically proven bladder cancer and 210 age- and gender-matched healthy controls was conducted. The genotypes of 3 common polymorphisms (-429 C/T, +1046 T/A and +1995 A/C) of the IL-22 gene were determined with fluorogenic 5' exonuclease assays. RESULTS: Patients with bladder cancer had a significantly higher frequency of the IL-22 -429 TT genotype [odds ratio (OR)=2.04, 95% confidence interval (CI)=1.19, 3.49; p=0.009] and -429 T allele (OR=1.42, 95% CI=1.08, 1.87; p=0.01) than the healthy controls. These findings were still significant after a Bonferroni correction. When stratifying according to the stage of bladder cancer, we found that patients with superficial bladder cancer had a significantly lower frequency of the IL-22 -429 TT genotype (OR=0.48, 95% CI=0.23, 0.98; p=0.04). When stratifying according to the grade and histological type of bladder cancer, we found no statistical association. The IL-22 +1046 T/A and IL-22 +1995 A/C gene polymorphisms were not associated with the risk of bladder cancer. CONCLUSION: To the authors' knowledge, this is the first report documenting that the IL-22 -429 C/T gene polymorphism is associated with bladder cancer risk. Additional studies are required to confirm this finding.

Association between interleukin-22 genetic polymorphisms and bladder cancer risk

OBJECTIVE:The cytokine interleukin-22 (IL-22), which is produced by T cells and natural killer cells, is associated with tumorigenesis and tumor progression in cancers. However, the role of IL-22 in bladder cancer has not been investigated.MATERIALS AND METHODS:A prospective hospital-based case-control study comprising 210 patients with pathologically proven bladder cancer and 210 age- and gender-matched healthy controls was conducted. The genotypes of 3 common polymorphisms (-429 C/T, +1046 T/A and +1995 A/C) of the IL-22 gene were determined with fluorogenic 5' exonuclease assays.RESULTS:Patients with bladder cancer had a significantly higher frequency of the IL-22 -429 TT genotype [odds ratio (OR)=2.04, 95% confidence interval (CI)=1.19, 3.49; p=0.009] and -429 T allele (OR=1.42, 95% CI=1.08, 1.87; p=0.01) than the healthy controls. These findings were still significant after a Bonferroni correction. When stratifying according to the stage of bladder cancer, we found that patients with superficial bladder cancer had a significantly lower frequency of the IL-22 -429 TT genotype (OR=0.48, 95% CI=0.23, 0.98; p=0.04). When stratifying according to the grade and histological type of bladder cancer, we found no statistical association. The IL-22 +1046 T/A and IL-22 +1995 A/C gene polymorphisms were not associated with the risk of bladder cancer.CONCLUSION:To the authors' knowledge, this is the first report documenting that the IL-22 -429 C/T gene polymorphism is associated with bladder cancer risk. Additional studies are required to confirm this finding.

The molecular basis for functional plasticity in type I interferon signaling.

Type I interferons (IFNs) are best known for their role in innate immunity, but they are also involved in other functions including immunomodulation, restricting proliferation, cancer surveillance, and the regulation of the adaptive immune response. All these responses are mediated through the interaction with a single cell surface receptor, albeit at different ligand and receptor concentrations, ligand subtypes, and time of activation. Here we review the functional plasticity of IFN signaling from a quantitative perspective, showing how variations in different ingredients of the system lead to differential IFN responses and how cells tune the system to maximize efficiency while minimizing detrimental effects. We present a basic model wherein the integrated action of different feedback mechanisms can provide sufficient temporal control to differentially drive cellular decisions.

Interferons and viruses: an evolutionary arms race of molecular interactions.

Over half a century has passed since interferons (IFNs) were discovered and shown to inhibit virus infection in cultured cells. Since then, researchers have steadily brought to light the molecular details of IFN signaling, catalogued their pleiotropic effects on cells, and harnessed their therapeutic potential for a variety of maladies. While advances have been plentiful, several fundamental questions have yet to be answered and much complexity remains to be unraveled. We explore the current knowledge surrounding four main questions: are type I IFN subtypes differentially produced in response to distinct pathogens? How are IFN subtypes distinguished by cells? What are the mechanisms and consequences of viral antagonism? Lastly, how can the IFN response be harnessed to improve vaccine efficacy?

Functional characterization of canine interferon-lambda.

In this study, we provide the first comprehensive annotation of canine interferon-λ (CaIFN-λ, type III IFN). Phylogenetic analysis based on genomic sequences indicated that CaIFN-λ is located in the same branch with Swine IFN-λ1 (SwIFN-λ), Bat IFN-λ1 (BaIFN-λ), and human IFN-λ1 (HuIFN-λ1). CaIFN-λ was cloned, expressed in Escherichia coli, and purified to further investigate the biological activity in vitro. The recombinant CaIFN-λ (rCaIFN-λ) displayed potent antiviral activity on both homologous and heterologous animal cells in terms of inhibiting the replication of the New Jersey serotype of vesicular stomatitis virus (VSV), canine parvovirus, and influenza virus A/WSN/33 (H1N1), respectively. In addition, we also found that rCaIFN-λ exhibits a significant antiproliferative response against A72 canine tumor cells and MDCK cells in a dose-dependent manner. Furthermore, CaIFN-λ activated the JAK-STAT signaling pathway. To evaluate the expression of CaIFN-λ induced by virus and the expression of IFN-stimulated genes (ISGs) induced by rCaIFN-λ in the MDCK cells, we measured the relative mRNA level of CaIFN-λ and ISGs (ISG15, Mx1, and 2'5'-OAS) by quantitative real-time PCR and found that the mRNA level of CaIFN-λ and the ISGs significantly increased after treating the MDCK cells with viruses and rCaIFN-λ protein, respectively. Finally, to evaluate the binding activity of rCaIFN-λ to its receptor, we expressed the extracellular domain of the canine IFN-λ receptor 1 (CaIFN-λR1-EC) and determined the binding activity via ELISA. Our results demonstrated that rCaIFN-λ bound tightly to recombinant CaIFN-λR1-EC (rCaIFN-λR1-EC).

Interleukins (ILs), a fascinating family of cytokines. Part I: ILs from IL-1 to IL-19.

Every nucleated cell can produce and respond to cytokines, extracellular proteic/glycoproteic mediators that constitute a complex, interconnected, and flexible signaling network, addressed to modulate cell behavior and homeostasis through the interaction with high-affinity surface receptors. These messenger molecules, whose main characteristics are potency, pleiotropism, and redundancy, primarily act in autocrine, paracrine, and juxtacrine way, but can also display systemic activity in endocrine-like modality. They are generally classified according to their cellular sources, three-dimensional structure, or biological functions. Among cytokines, interleukins (ILs) represent a fascinating and multifunctional group of immunomodulators that primarily mediate the leukocyte cross-talk (hence the name), and mainly regulate the immune cell proliferation, differentiation, growth, survival, activation, and functions. Up to 38 ILs have been so far identified, numbered according to the order of discovery, and grouped in different subsets, based on distinguishing structural/functional features. Due to their crucial role in regulating inflammation and immune response, ILs are known to be involved in the pathogenesis of human inflammatory/autoimmune diseases. Therefore, they have increasingly attracted great interest as effective or promising therapeutic targets. The biology and functions of the hitherto identified human ILs are reviewed and discussed: in this first section of the article, ILs from IL-1 to IL-19 are presented.