IL-22 Binding Protein (IL-22BP) in the Regulation of IL-22 Biology.

Cytokines are powerful mediators of inflammation. Consequently, their potency is regulated in many ways to protect the host. Several cytokines, including IL-22, have coordinating binding proteins or soluble receptors that bind to the cytokine, block the interaction with the cellular receptor, and thus prevent cellular signaling. IL-22 is a critical cytokine in the modulation of tissue responses during inflammation and is highly upregulated in many chronic inflammatory disease patients, including those with psoriasis, rheumatoid arthritis, and inflammatory bowel disease (IBD). In healthy individuals, low levels of IL-22 are secreted by immune cells, mainly in the gastrointestinal (GI) tract. However, much of this IL-22 is likely not biologically active due to the high levels of IL-22 binding protein (IL-22BP) produced by intestinal dendritic cells (DCs). IL-22BP is a soluble receptor homolog that binds to IL-22 with greater affinity than the membrane spanning receptor. Much is known regarding the regulation and function of IL-22 in health and disease. However, less is known about IL-22BP. In this review, we will focus on IL-22BP, including its regulation, role in IL-22 biology and inflammation, and promise as a therapeutic. IL-22 can be protective or pathogenic, depending on the context of inflammation. IL-22BP also has divergent roles. Ongoing and forthcoming studies will expand our knowledge of IL-22BP and IL-22 biology, and suggest that IL-22BP holds promise as a way to regulate IL-22 biology in patients with chronic inflammatory disease.

Retinoic acid-responsive CD8 effector T cells are selectively increased in IL-23-rich tissue in gastrointestinal GVHD.

Gastrointestinal (GI) graft-versus-host disease (GVHD) is a major barrier in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The metabolite retinoic acid (RA) potentiates GI-GVHD in mice via alloreactive T cells expressing the RA receptor-α (RARα), but the role of RA-responsive cells in human GI-GVHD remains undefined. Therefore, we used conventional and novel sequential immunostaining and flow cytometry to scrutinize RA-responsive T cells in tissues and blood of patients who had received allo-HSCT and to characterize the impact of RA on human T-cell alloresponses. Expression of RARα by human mononuclear cells was increased after exposure to RA. RARαhi mononuclear cells were increased in GI-GVHD tissue, contained more cellular RA-binding proteins, localized with tissue damage, and correlated with GVHD severity and mortality. By using a targeted candidate protein approach, we predicted the phenotype of RA-responsive T cells in the context of increased microenvironmental interleukin-23 (IL-23). Sequential immunostaining confirmed the presence of a population of RARαhi CD8 T cells with the predicted phenotype that coexpressed the effector T-cell transcription factor T-bet and the IL-23-specific receptor (IL-23R). These cells were increased in GI- but not skin-GVHD tissues and were also selectively expanded in the blood of patients with GI-GVHD. Finally, functional approaches demonstrated that RA predominantly increased alloreactive GI-tropic RARαhi CD8 effector T cells, including cells with the phenotype identified in vivo. IL-23-rich conditions potentiated this effect by selectively increasing ß7 integrin expression on CD8 effector T cells and reducing CD4 T cells with a regulatory cell phenotype. In summary, we have identified a population of RA-responsive effector T cells with a distinctive phenotype that is selectively expanded in human GI-GVHD and that represents a potential new therapeutic target.

Pathophysiologic mechanisms of itch in bullous pemphigoid.

BACKGROUND: One of the hallmarks of bullous pemphigoid (BP) is moderate to severe chronic itch. Managing this is difficult because little is known about the mechanisms of itch in BP. OBJECTIVE: We sought to elucidate the pathophysiologic mechanisms of itch in BP. METHODS: The expression of itch mediators in lesions of 24 patients with BP and 6 healthy individuals were examined through immunofluorescence staining. Furthermore, the expression of itch mediators and itch severity was correlated. RESULTS: Itch severity was correlated with eosinophils, substance P, neurokinin 1R, interleukin (IL) 31 receptor A, oncostatin M receptor-ß, IL-13, periostin, and basophils. There was also a trend between itch severity and IL-31 expression. Most of the cells expressing IL-31 or neurokinin 1R were identified as eosinophils. Intraepidermal nerve fiber density was decreased. Other itch mediators, including mast cells, IL-4, thymic stromal lymphopoietin, transient receptor potential vanilloid 1 and ankyrin 1, and protease activated receptor 2 were not significantly correlated with itch severity. LIMITATIONS: The relatively small sample size, the examination of protein expression exclusively through immunofluorescent analysis, and lack of functional assays in patients are the limitations. CONCLUSIONS: Multiple factors are involved in BP-associated itch, including eosinophils, substance P, neurokinin 1R, IL-31, IL-31 receptor A, oncostatin M receptor-ß, IL-13, periostin, and basophils. They could be useful therapeutic targets.

A longitudinal study highlights shared aspects of the transcriptomic response to cardiogenic and septic shock.

BACKGROUND: Septic shock (SS) and cardiogenic shock (CS) are two types of circulatory shock with a different etiology. Several studies have described the molecular alterations in SS patients, whereas the molecular factors involved in CS have been poorly investigated. We aimed to assess in the whole blood of CS and SS patients, using septic patients without shock (SC) as controls, transcriptomic modifications that occur over 1 week after ICU admission and are common to the two types of shock. METHODS: We performed whole blood RNA sequencing in 21 SS, 11 CS, and 5 SC. In shock patients, blood samples were collected within 16 h from ICU admission (T1), 48 h after ICU admission (T2), and at day 7 or before discharge (T3). In controls, blood samples were available at T1 and T2. Gene expression changes over time have been studied in CS, SS, and SC separately with a paired analysis. Genes with p value < 0.01 (Benjamini-Hochberg multiple test correction) were defined differentially expressed (DEGs). We used gene set enrichment analysis (GSEA) to identify the biological processes and transcriptional regulators significantly enriched in both types of shock. RESULTS: In both CS and SS patients, GO terms of inflammatory response and pattern recognition receptors (PRRs) were downregulated following ICU admission, whereas gene sets of DNA replication were upregulated. At the gene level, we observed that alarmins, interleukin receptors, PRRs, inflammasome, and DNA replication genes significantly changed their expression in CS and SS, but not in SC. Analysis of transcription factor targets showed in both CS and SS patients, an enrichment of CCAAT-enhancer-binding protein beta (CEBPB) targets in genes downregulated over time and an enrichment of E2F targets in genes with an increasing expression trend. CONCLUSIONS: This pilot study supports, within the limits of a small sample size, the role of alarmins, PRRs, DNA replication, and immunoglobulins in the pathophysiology of circulatory shock, either in the presence of infection or not. We hypothesize that these genes could be potential targets of therapeutic interventions in CS and SS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02141607. Registered 19 May 2014.

Several genes involved in the JAK-STAT pathway may act as prognostic markers in pancreatic cancer identified by microarray data analysis.

PURPOSE: This study aimed to identify the underlying mechanisms in pancreatic cancer (PC) carcinogenesis and those as potential prognostic biomarkers, which can also be served as new therapeutic targets of PC. METHODS: Differentially expressed genes (DEGs) were identified between PC tumor tissues and adjacent normal tissue samples from a public GSE62452 dataset, followed by functional and pathway enrichment analysis. Then, protein-protein interaction (PPI) network was constructed and prognosis-related genes were screened based on genes in the PPI network, before which prognostic gene-related miRNA regulatory network was constructed. Functions of the prognostic gene in the network were enriched before which Kaplan-Meier plots were calculated for significant genes. Moreover, we predicted related drug molecules based on target genes in the miRNA regulatory network. Furthermore, another independent GSE60979 dataset was downloaded to validate the potentially significant genes. RESULTS: In the GSE62452 dataset, 1017 significant DEGs were identified. Twenty-six important prognostic-related genes were found using multivariate Cox regression analysis. Through pathway enrichment analysis and miRNA regulatory analysis, we found that the 5 genes, such as Interleukin 22 Receptor Subunit Alpha 1 (IL22RA1), BCL2 Like 1 (BCL2L1), STAT1, MYC Proto-Oncogene (MYC), and Signal Transducer And Activator Of Transcription 2 (STAT2), involved in the Jak-STAT signaling pathway were significantly associated with prognosis. Moreover, the expression change of these 5 genes was further validated using another microarray dataset. Additionally, we identified camptothecin as an effective drug for PC. CONCLUSION: IL22RA1, BCL2L1, STAT1, MYC, and STAT2 involved in the Jak-STAT signaling pathway may be significantly associated with prognosis of PC.

Ultrasound targeting of Q-starch/miR-197 complexes for topical treatment of psoriasis.

Psoriasis is a common, worldwide autoinflammatory, incurable skin disease. miR-197 has therapeutic potential for psoriasis since it can down-regulate the expression of both IL-22RA1 and IL-17RA, subunits of the receptors of IL-22 and IL-17, respectively, which are key cytokines in the disease. Although miR-197 has the potential to treat the disease, several inherent physical barrier properties of the skin challenge miRNA's delivery to the target skin cells. In the present study, we evaluated a therapeutic approach that combines the use of ultrasound (US) as a means to enhance skin permeability with quaternized starch (Q-starch) as an miRNA delivery carrier. This resulted in decreased expression of the miR-197 target proteins and in a significant reduction in the psoriatic activity markers. Our results demonstrate the potential of combinations of US and Q-starch/miR-197 complexes for the topical skin treatment of psoriasis.

Screening of Differentiation-Specific Molecular Biomarkers for Colon Cancer.

BACKGROUND/AIMS: Owing to the lack of effective molecular markers to evaluate colon cancer differentiation grade, screening of effective molecular markers for the diagnosis and treatment of colon cancer is of great significance. This study is a screening study for molecular markers related to the differentiation of colon using the tissue-specific genes of colon. METHODS: This study compared the expression profiles of colon cancer at various differentiation grades and screened the down-regulated genes associated with decreased differentiation. IL22RA1 gene was derived from the intersection of obtained gene and colon tissue-specific genes. We used DriverDB and The Human Protein Atlas to analyze the expression level of IL22RA1 in various tissue cells, also used Kaplan-Meier method to analyze the correlation between IL22RA1 and the survival of colon cancer patients, and then used the ROC curve to analyze the specificity and sensitivity of IL22RA1 diagnosis of differentiated colon cancer. RESULTS: We found that IL22RA1 gene expression was progressively down-regulated in high-differentiated, moderate-differentiated, low-differentiated, and undifferentiated colon cancer tissues. Both RNA and protein levels of IL22RA1 were higher in colon tissues and colon cancer tissues than in other normal and cancer tissues. Comparison of IL22RA1 expression in different cancer cells found that IL22RA1 expression was significantly higher in CACO-2 colon cancer cells than in other cancer cells. Survival analysis showed that IL22RA1 gene expression was positively correlated with the overall survival rate of colon cancer patients (P=0.0224). ROC curve analysis revealed that IL22RA1 expression had good specificity and sensitivity to stage II colon cancer. CONCLUSION: These findings suggest that IL22RA1 serves as a specific molecular marker for the differentiation of colon cancer.

Regulation of IL-22BP in psoriasis.

IL-22 is a potent pro-inflammatory cytokine upregulated in psoriasis and in other inflammatory diseases. The function of IL-22 is regulated by the soluble scavenging receptor, IL-22 binding protein (IL-22BP or IL-22RA2). However, the role and regulation of IL-22BP itself in the pathogenesis of inflammatory disease remain unclear. We used the TLR7 agonist Imiquimod (IMQ) to induce a psoriasis-like skin disease in mice and found a strong downregulation of IL-22BP in the affected skin as well as in the lymph nodes of animals treated with IMQ. We also analysed psoriatic skin of patients and compared this to skin of healthy donors. Interestingly, IL-22BP expression was similarly downregulated in skin biopsies of psoriasis patients compared to the skin of healthy donors. Since IL-22BP is expressed foremost in dendritic cells, we characterized its expression in monocyte-derived dendritic cells (MoDC) during maturation. In this way, we found Prostaglandin E2 (PGE2) to be a potent suppressor of IL-22BP expression in vitro. We conclude that regulation of IL-22BP by inflammatory mediators is an important step for the progression of inflammation in the skin and possibly also in other autoimmune diseases.

Interleukin-22 level is negatively correlated with neutrophil recruitment in the lungs in a Pseudomonas aeruginosa pneumonia model.

Pseudomonas aeruginosa is a major threat for immune-compromised patients. Bacterial pneumonia can induce uncontrolled and massive neutrophil recruitment ultimately leading to acute respiratory distress syndrome and epithelium damage. Interleukin-22 plays a central role in the protection of the epithelium. In this study, we aimed to evaluate the role of interleukin-22 and its soluble receptor IL-22BP in an acute Pseudomonas aeruginosa pneumonia model in mice. In this model, we noted a transient increase of IL-22 during Pseudomonas aeruginosa challenge. Using an antibody-based approach, we demonstrated that IL-22 neutralisation led to increased susceptibility to infection and to lung damage correlated with an increase in neutrophil accumulation in the lungs. On the contrary, rIL-22 administration or IL-22BP neutralisation led to a decrease in mouse susceptibility and lung damage associated with a decrease in neutrophil accumulation. This study demonstrated that the IL-22/IL-22BP system plays a major role during Pseudomonas aeruginosa pneumonia by moderating neutrophil accumulation in the lungs that ultimately leads to epithelium protection.

The Role of IL-27 and its Receptor in the Pathogenesis of HIV/AIDS and Anti-viral Immune Response.

BACKGROUND: Cytokines have been widely demonstrated to involve in the pathogenesis of AIDS and the mechanisms of antiretroviral therapy. Interleukin 27 (IL-27) is a new member of the IL-12 cytokine family and has been shown to interfere HIV-1 virus replication with controversial findings. This study is to investigate the dynamic changes in plasma IL-27 level and cell surface IL-27 receptor expression in HIV/AIDS patients who underwent HAART. METHODS: Whole blood was collected from 34 HIV-positive/AIDS patients 0, 6, and 12 months after initiation of HAART and 27 healthy subjects. Plasma IL-27, IFN-γ, and IL-4 were measured by enzyme-linked immunosorbent assay, while peripheral blood CD3+CD4+ T cells count and the gp130 expressed CD3+CD4+cell were measured by flow cytometry. RESULTS: The plasma IL-27 concentration, IFN-γ concentration, and percentage of positive gp130 CD4 cells were significantly decreased in previously treatment-naive HIV/AIDS patients compared to healthy controls, but gradually increased 6 and 12 months after initiation of HAART. Conversely, IL-4 levels were significantly increased in treatment-naive HIV/AIDS patients compared to healthy controls, but gradually decreased 6 and 12 months after HAART. The concentrations of plasma IL-27 were positively correlated with the percentage of gp130 positive CD4 cells (r=0.438, p=0.016). Both plasma IL-27 concentration and gp130 positive cell percentage were positively associated with peripheral blood CD3+CD4+ T cell count (P<0.05 or P<0.01), but negatively associated with plasma HIV viral load (P<0.05 or P<0.01). CONCLUSION: IL-27 signaling (IL-27 and its receptor) may be involved in the pathogenesis of HIV infection and immune reconstitution in HIV/AIDS patients who underwent HAART. IL-27 may exert effects through regulating Th1 / Th2 ratio.

Role of interleukin-23 in monocyte-derived dendritic cells of HBV-related acute-on-chronic liver failure and its correlation with the severity of liver damage.

BACKGROUND: The role of interleukin-23 (IL-23) in monocyte-derived dendritic cells (MoDCs) from hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients remains unclear. The aim of this study was to observe the correlation between the activation of the IL-23 signaling pathway and the prognosis of HBV-ACLF patients. MATERIALS AND METHODS: The baseline levels of serum IL-6, IL-12, IL-17, IL-23, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) from immune tolerant (IT), chronic hepatitis B (CHB), HBV-ACLF patients and healthy individuals who served as healthy controls (HCs) were analyzed using the Luminex system, whereas serum IL-23 from HBV-ACLF patients was measured by ELISA before and after treatment. Purified monocytes were isolated from peripheral blood and were induced into MoDCs, IL-23, IL-23R, NF-κB and TRAF6 expression in MoDCs from 4 groups was analyzed using real-time PCR, and IL-23R and intracellular IL-23 were evaluated by flow cytometry. RESULTS: Serum IL-6, IL-12, IL-17, IL-23 and TNF-α levels were upregulated in HBV-ACLF patients compared with IT patients, CHB patients and HCs (P<0.05 for all). Serum IL-23 was closely correlated with elevated serum IL-17 in HBV-ACLF patients (r=0.5935, P<0.0001). Moreover, IL-23 and IL-23R levels were significantly upregulated in MoDCs from patients with CHB or HBV-ACLF compared with HCs, and further upregulation of IL-23 and IL-23R was observed in HBV-ACLF patients compared to CHB patients (P<0.05 for all). IL-23 expression was markedly enhanced and was correlated with elevated NF-κB and TRAF6 in MoDCs from HBV-ACLF patients (P<0.05 for both). Linear correlation analysis demonstrated significant correlations between the expression of IL-23 and disease severity markers (MELD scoring system, international normalized ratio, prothrombin time and total bilirubin, r=0.6874, r=0.6475, r=0.6249, r=0.3771, respectively, P<0.05 for all) for individual HBV-ACLF patients, and IL-23 levels were significantly upregulated in non-survival HBV-ACLF patients compared with survival HBV-ACLF patients (P<0.05). CONCLUSION: IL-23 in serum and MoDCs is significantly elevated in HBV-ACLF patients, TRAF6/NF-κB may play a role in IL-23 production by MoDCs in HBV-ACLF patients and high pre-treatment IL-23 levels in MoDCs are associated with mortality in HBV-ACLF patients.

Sodium chloride-enriched Diet Enhanced Inflammatory Cytokine Production and Exacerbated Experimental Colitis in Mice.

BACKGROUND AND AIM: Environmental factors are supposed to play a decisive role in the pathogenesis of inflammatory bowel diseases [IBDs]. Increased dietary salt intake has been linked with the development of autoimmune diseases, but the impact of a salt-enriched diet on the course of IBD remains unknown. In this study, we examined whether high salt intake alters mucosal cytokine production and exacerbates colitis. METHODS: Normal intestinal lamina propria mononuclear cells [LPMCs] were activated with anti-CD3/CD28 in the presence or absence of increasing concentrations of sodium chloride [NaCl] and/or SB202190, a specific inhibitor of p38/MAP Kinase. For in vivo experiments, a high dose of NaCl was administered to mice 15 days before induction of trinitrobenzene-sulfonic acid [TNBS]-colitis or dextran sulfate sodium [DSS]-colitis. In parallel, mice were given SB202190 before induction of TNBS-colitis. Transcription factors and effector cytokines were evaluated by flow-cytometry and real-time PCR. RESULTS: IL-17A, IL-23R, TNF-α, and Ror-γT were significantly increased in human LPMCs following NaCl exposure, while there was no significant change in IFN-γ, T-bet or Foxp3. Pharmacologic inhibition of p38/MAPK abrogated the NaCl-inducing effect on LPMC-derived cytokines. Mice receiving the high-salt diet developed a more severe colitis than control mice, and this effect was preventable by SB202190. CONCLUSIONS: Our data indicated that exposure of intestinal mononuclear cells to a high-NaCl diet enhanced effector cytokine production and contributed to the exacerbation of experimental colitis in mice.

Aryl Hydrocarbon Receptor Ligands in Cigarette Smoke Induce Production of Interleukin-22 to Promote Pancreatic Fibrosis in Models of Chronic Pancreatitis.

BACKGROUND & AIMS: Cigarette smoke has been identified as an independent risk factor for chronic pancreatitis (CP). Little is known about the mechanisms by which smoking promotes development of CP. We assessed the effects of aryl hydrocarbon receptor (AhR) ligands found in cigarette smoke on immune cell activation in humans and pancreatic fibrosis in animal models of CP. METHODS: We obtained serum samples from patients with CP treated at Stanford University hospital and healthy individuals (controls) and isolated CD4+ T cells. Levels of interleukin-22 (IL22) were measured by enzyme-linked immunosorbent assay and smoking histories were collected. T cells from healthy nonsmokers and smokers were stimulated and incubated with AhR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin or benzo[a]pyrene) or antagonists and analyzed by flow cytometry. Mice were given intraperitoneal injections of caerulein or saline, with or without lipopolysaccharide, to induce CP. Some mice were given intraperitoneal injections of AhR agonists at the start of caerulein injection, with or without an antibody against IL22 (anti-IL22) starting 2 weeks after the first caerulein injection, or recombinant mouse IL22 or vehicle (control) intraperitoneally 4 weeks after the first caerulein injection. Mice were exposed to normal air or cigarette smoke for 6 h/d for 7 weeks and expression of AhR gene targets was measured. Pancreata were collected from all mice and analyzed by histology and quantitative reverse transcription polymerase chain reaction. Pancreatic stellate cells and T cells were isolated and studied using immunoblot, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent analyses. RESULTS: Mice given AhR agonists developed more severe pancreatic fibrosis (based on decreased pancreas size, histology, and increased expression of fibrosis-associated genes) than mice not given agonists after caerulein injection. In mice given saline instead of caerulein, AhR ligands did not induce fibrosis. Pancreatic T cells from mice given AhR agonists and caerulein were activated and expressed IL22, but not IL17 or interferon gamma. Human T cells exposed to AhR agonists up-regulated expression of IL22. In mice given anti-IL22, pancreatic fibrosis did not progress, whereas mice given recombinant IL22 had a smaller pancreas and increased fibrosis. Pancreatic stellate cells isolated from mouse and human pancreata expressed the IL22 receptor IL22RA1. Incubation of the pancreatic stellate cells with IL22 induced their expression of the extracellular matrix genes fibronectin 1 and collagen type I α1 chain, but not α2 smooth muscle actin or transforming growth factor-ß. Serum samples from smokers had significantly higher levels of IL22 than those from nonsmokers. CONCLUSIONS: AhR ligands found in cigarette smoke increase the severity of pancreatic fibrosis in mouse models of pancreatitis via up-regulation of IL22. This pathway might be targeted for treatment of CP and serve as a biomarker of disease.

The interleukin-20 receptor axis in early rheumatoid arthritis: novel links between disease-associated autoantibodies and radiographic progression.

BACKGROUND: Rheumatoid arthritis (RA) is often characterized by the presence of rheumatoid factor, anti-citrullinated protein antibodies, and bone erosions. Current therapies can compromise immunity, leading to risk of infection. The interleukin-20 receptor (IL-20R) axis comprising IL-19, IL-20, and IL-24 and their shared receptors activates tissue homeostasis processes but not the immune system. Consequently, modulation of the IL-20R axis may not lead to immunosuppression, making it an interesting drug target. We evaluated the role of the IL-20R axis in RA and associations between plasma cytokine levels and clinical disease. METHODS: Plasma IL-19, IL-20, and IL-24 levels were measured in early RA patients during a treat-to-target strategy by enzyme-linked immunosorbent assays. The IL-20R1 and IL-22R1 levels in paired peripheral blood mononuclear cells and synovial fluid mononuclear cells from a different cohort of RA patients were evaluated by flow cytometry and confocal microscopy. Monocytes/macrophages were stimulated with heat-aggregated human immunoglobulin immune complexes and immune complexes containing citrullinated fibrinogen, and osteoclasts were incubated with IL-19, IL-20, and IL-24. RESULTS: The plasma concentrations of IL-20 and IL-24 (but not IL-19) were increased in early RA patients compared with healthy controls (both P < 0.002) and decreased after 6 months of treatment (both P < 0.0001). The expression of IL-22R1 (but not IL-20R1) was increased on monocytes from RA synovial fluid compared with monocytes from both RA and healthy control peripheral blood. The plasma concentrations of IL-20 and IL-24 were increased in rheumatoid factor and anti-citrullinated protein antibody positive compared with negative early RA patients (all P < 0.0001). Immune complexes stimulated the production of the IL-20R cytokines by monocytes/macrophages. Increased baseline plasma concentrations of IL-20 and IL-24 were associated with Sharp-van der Heijde score progression after 24 months (Spearman's rho = 0.19 and 0.26, both P < 0.05) in the early RA patients. The IL-22R1 was expressed by osteoclast precursors and in multinucleated osteoclasts. IL-20 and IL-24 increased the secretion of monocyte chemoattractant protein 1 by these cells. CONCLUSIONS: This study suggests that IL-20 and IL-24 link RA-associated autoantibodies with radiographic progression via the IL-22R1. Modulation of this axis holds promise as feasible anti-erosive treatment modalities in seropositive RA.

Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis.

Ectopic lymphoid-like structures (ELSs) reminiscent of secondary lymphoid organs often develop at sites of chronic inflammation where they contribute to immune-mediated pathology. Through evaluation of synovial tissues from rheumatoid arthritis (RA) patients, we now show that low interleukin-27 (IL-27) expression corresponds with an increased incidence of ELS and gene signatures associated with their development and activity. The presence of synovial ELS was also noted in mice deficient in the IL-27 receptor (IL-27R) after the onset of inflammatory arthritis. Here, pathology was associated with increased synovial expression of pro-inflammatory cytokines, homeostatic chemokines, and transcriptional regulators linked with lymphoid neogenesis. In both clinical and experimental RA, synovial ELS coincided with the heightened local expression of cytokines and transcription factors of the Th17 and T follicular helper (Tfh) cell lineages, and included podoplanin-expressing T cells within lymphoid aggregates. IL-27 inhibited the differentiation of podoplanin-expressing Th17 cells, and an increased number of these cells were observed in IL-27R-deficient mice with inflammatory arthritis. Thus, IL-27 appears to negatively regulate ELS development in RA through control of effector T cells. These studies open new opportunities for patient stratification and treatment.

Expression of interleukin-22 and its significance in the pathogenesis of chronic rhinosinusitis.

In order to explore the role of IL-22 in the pathogenesis of CRS, we observed the expression of IL-22 and associated factors in chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP). Immunohistochemical staining was applied to detect the expression of IL-22, IL-22R, STAT3, retinoic acid orphan receptor C (RORC) and aryl hydrocarbon recptor (AhR). There was significantly higher expression of IL-22 in CRSsNP than in controls (P<0.05). But the expression of IL-22 had no significant difference when comparing CRSwNP with CRSsNP and controls. The expression of IL-22R was significantly lower in CRSwNP compared to controls and CRSsNP (P<0.05). The expression of AhR was lower in CRSwNP than in CRSsNP (P<0.05). There was no significant difference of RORC and STAT3 among CRSwNP, CRSsNP and controls. IL-22 plays the important role in the pathogenesis of CRS, and further research is needed to understand the complex interactions with other cytokines and the exact mechanism of transcriptional regulation for IL-22.

Genome-based risk prediction for early stage breast cancer.

Tests to better characterize tumor genomic architecture are quickly becoming a standard of care in oncology. For breast cancer, the use of gene expression assays for early stage disease is already common practice. These tests have found a place in risk stratifying the heterogeneous group of stage I-II breast cancers for recurrence, for predicting chemotherapy response, and for predicting breast cancer-related mortality. In the last 5 years, more assays have become available to the practicing oncologist. Given the rapidity with which this field has evolved, it is prudent to review the tests, their indications, and the studies from which they have been validated. We present a comprehensive review of the available gene expression assays for early stage breast cancer. We review data for several individual tests and comparative studies looking at risk prediction and cost-effectiveness.

Prediction of late disease recurrence and extended adjuvant letrozole benefit by the HOXB13/IL17BR biomarker.

BACKGROUND: Biomarkers to optimize extended adjuvant endocrine therapy for women with estrogen receptor (ER)-positive breast cancer are limited. The HOXB13/IL17BR (H/I) biomarker predicts recurrence risk in ER-positive, lymph node-negative breast cancer patients. H/I was evaluated in MA.17 trial for prognostic performance for late recurrence and treatment benefit from extended adjuvant letrozole. METHODS: A prospective-retrospective, nested case-control design of 83 recurrences matched to 166 nonrecurrences from letrozole- and placebo-treated patients within MA.17 was conducted. Expression of H/I within primary tumors was determined by reverse-transcription polymerase chain reaction with a prespecified cutpoint. The predictive ability of H/I for ascertaining benefit from letrozole was determined using multivariable conditional logistic regression including standard clinicopathological factors as covariates. All statistical tests were two-sided. RESULTS: High H/I was statistically significantly associated with a decrease in late recurrence in patients receiving extended letrozole therapy (odds ratio [OR] = 0.35; 95% confidence interval [CI] = 0.16 to 0.75; P = .007). In an adjusted model with standard clinicopathological factors, high H/I remained statistically significantly associated with patient benefit from letrozole (OR = 0.33; 95% CI = 0.15 to 0.73; P = .006). Reduction in the absolute risk of recurrence at 5 years was 16.5% for patients with high H/I (P = .007). The interaction between H/I and letrozole treatment was statistically significant (P = .03). CONCLUSIONS: In the absence of extended letrozole therapy, high H/I identifies a subgroup of ER-positive patients disease-free after 5 years of tamoxifen who are at risk for late recurrence. When extended endocrine therapy with letrozole is prescribed, high H/I predicts benefit from therapy and a decreased probability of late disease recurrence.

Interleukin-22 is frequently expressed in small- and large-cell lung cancer and promotes growth in chemotherapy-resistant cancer cells.

INTRODUCTION: In lung cancer, interleukin-22 (IL-22) expression within primary tissue has been demonstrated, but the frequency and the functional consequence of IL-22 signaling have not been addressed. This study aims at analyzing the cellular effects of IL-22 on lung carcinoma cell lines and the prognostic impact of IL-22 tissue expression in lung cancer patients. METHODS: Biological effects of IL-22 signaling were investigated in seven lung cancer cell lines by Western blot, flow cytometry, real-time polymerase chain reaction, and proliferation assays. Tumor tissue specimens of two cohorts with a total of 2300 lung cancer patients were tested for IL-22 expression by immunohistochemistry. IL-22 serum concentrations were analyzed in 103 additional patients by enzyme-linked immunosorbent assay. RESULTS: We found the IL-22 receptor 1 (IL-22-R1) to be expressed in six of seven lung cancer cell lines. However IL-22 signaling was functional in only four cell lines, where IL-22 induced signal transducer activator of transcription 3 phosphorylation and increased cell proliferation. Furthermore, IL-22 induced the expression of antiapoptotic B-cell lymphoma 2, but did not rescue tumor cells from carboplatin-induced apoptosis. Cisplatin-resistant cell lines showed a significant up-regulation of IL-22-R1 along with a stronger proliferative response to IL-22 stimulation. IL-22 was preferentially expressed in small- and large-cell lung carcinoma (58% and 46% of cases, respectively). However, no correlation between IL-22 expression by immunohistochemistry and prognosis was observed. CONCLUSION: IL-22 is frequently expressed in lung cancer tissue. Enhanced IL-22-R1 expression and signaling in chemotherapy-refractory cell lines are indicative of a protumorigenic function of IL-22 and may contribute to a more aggressive phenotype.

Intravenously delivered graphene nanosheets and multiwalled carbon nanotubes induce site-specific Th2 inflammatory responses via the IL-33/ST2 axis.

Carbon-based nanomaterials (CBN), such as graphene nanosheets (GNS) and multiwalled carbon nanotubes (MWCNT), have been proposed for potential nanomedicine applications such as biomedical devices and carriers for drug delivery. However, our current understanding regarding the systemic toxicity of these CBN through intravenous (iv) injection is limited. In this study, we compare the immune response resulting from GNS and MWCNT exposure. We hypothesize that iv administration of GNS and MWCNT would result in divergent systemic inflammatory responses due to physicochemical differences between these two CBN. In the lungs of C57BL/6 mice, GNS actuate a Th2 immune response 1 day following iv administration, which consists of neutrophilic influx and a significant increase in interleukin (IL)-5, IL-13, IL-33, and its soluble receptor (sST2) in the bronchoalveolar lavage fluid. MWCNT elicited a significant increase in the messenger ribonucleic acid expression of cytokines in the spleen including IL-4 and IL-33, which are associated with an increase in splenic cell differentiation (CD)4(+) and CD8(+) T-cells in C57BL/6 mice following iv injection. The observed Th2 responses in both the lung and spleen are absent in ST2(-/-) mice administrated GNS or MWCNT, suggesting a critical role for IL-33. In conclusion, the use of GNS or MWCNT as nanocarriers for drug delivery may result in Th2 immune responses that are mediated through the IL-33/ST2 axis and therefore may promote adverse allergic reactions.