Crohn’s disease (CD), a form of inflammatory bowel disease (IBD), is characterized by impaired epithelial barrier functions and dysregulated mucosal immune responses. IL-22 binding protein (IL-22BP) is a soluble inhibitor regulating IL-22 bioactivity, a cytokine proposed to play protective roles during CD. We and others have shown that IL-22BP is produced in IBD inflamed tissues, hence suggesting a role in CD. In this work, we extended the characterization of IL-22BP production and distribution in CD tissues by applying enzyme-linked immunosorbent assays to supernatants obtained from the culture of endoscopic biopsies of patients, and reverse transcription-quantitative polymerase chain reaction on sorted immune cell subsets. We reveal that IL-22BP levels are higher in inflamed ileums than colons. We observe that in a cell-intrinsic fashion, populations of mononuclear phagocytes and eosinophils express IL-22BP at the highest levels in comparison to other sources of T cells. We suggest the enrichment of intestinal eosinophils could explain higher IL-22BP levels in the ileum. In inflamed colon, we reveal the presence of increased IL-22/IL22BP ratios compared to controls, and a strong correlation between IL-22BP and CCL24. We identify monocyte-derived dendritic cells (moDC) as a cellular subtype co-expressing both cytokines and validate our finding using in vitro culture systems. We also show that retinoic acid induces the secretion of both IL-22BP and CCL24 by moDC. Finally, we report on higher IL-22BP levels in active smokers. In conclusion, our work provides new information relevant to therapeutic strategies modulating IL-22 bioactivity in CD, especially in the context of disease location.

• Humans
• Carrier Proteins/metabolism
• Colon
• Crohn Disease
• Cytokines/metabolism
• Inflammatory Bowel Diseases
• Intestines/pathology

• Composition of microbiota
• Host health and diseases
• Immune system
• Microbial-derived antigens and metabolites
• Microbiota

In addition to β-cell failure with inadequate insulin secretion, the crucial mechanism leading to establishment of diabetes mellitus (DM) is the resistance of target cells to insulin, i.e. insulin resistance (IR), indicating a requirement of beyond-normal insulin concentrations to maintain euglycemic status and an ineffective strength of transduction signaling from the receptor, downstream to the substrates of insulin action. IR is a common feature of most metabolic disorders, particularly type II DM as well as some cases of type I DM. A variety of human inflammatory disorders with increased levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β, have been reported to be associated with an increased risk of IR. Autoimmune-mediated arthritis conditions, including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), with the involvement of proinflammatory cytokines as their central pathogenesis, have been demonstrated to be associated with IR, especially during the active disease state. There is an increasing trend towards using biologic agents and small molecule-targeted drugs to treat such disorders. In this review, we focus on the effects of anti-TNF-α- and non-TNF-α-targeted therapies on IR in patients with RA, PsA and AS. Anti-TNF-α therapy, IL-1 blockade, IL-6 antagonist, Janus kinase inhibitor and phospho-diesterase type 4 blocker can reduce IR and improve diabetic hyper-glycemia in autoimmune-mediated arthritis.

• Insulin resistance
• Diabetes mellitus
• Tumor necrosis factor-α-targeted therapy
• Non-tumor necrosis factor-α-targeted therapy
• Rheumatoid arthritis
• Psoriatic arthritis

• Periodontitis
• Single nucleotide polymorphisms
• Tumor necrosis factor - alpha
• Tumor necrosis factor receptors
• Type 2 diabetes mellitus

Current evidence highlights a link between insulin resistance (IR) and disease activity in rheumatoid arthritis (RA), suggesting that insulin sensitivity can be improved by treating patients with TNF‐α blockers. Although reduced IR has been shown in RA patients who receive monoclonal antibody treatment, the efficacy remains to be elucidated when using recombinant soluble receptor fusion proteins. In particular, etanercept (ETA) is capable of blocking lymphotoxin‐α, a cytokine‐related to IR‐associated disease status.

A prospective study was carried out in nondiabetic active RA patients receiving a 25‐mg subcutaneous ETA injection twice weekly.

Thirty patients aged 31 to 73 years (50.9 ± 10.6), naïve to biological and targeted synthetic disease‐modifying antirheumatic drugs with DAS28 scores of 5.17 to 7.49 (6.11 ± 0.66), were classified into high‐IR and low‐IR groups based on their baseline homeostatic model assessment (HOMA)‐IR levels. No differences were found between the two groups in terms of age, sex, weight, body mass index, seropositivity, and medication profiles before the injection. After a 24‐week therapeutic period, there were reduced HOMA‐IR levels in all patients in the high‐IR group (3.390 ± 0.636 to 2.234 ± 0.870, P < 0.001). A greater decrease in DAS28 values was found in patients with reduced IR than those without a reduction (2.54 ± 0.67 versus 1.46 ± 0.46, P = 0.006) in the low‐IR group.

We observed an improvement in insulin sensitivity in nondiabetic active RA patients following 24‐week recombinant soluble TNF‐α receptor fusion protein therapy.

• Adaptive Immunity
• Animals
• B-Lymphocytes/immunology
• Biological Evolution
• Immunity, Mucosal
• Lymphoid Tissue/immunology
• Mucous Membrane/pathology
• Neural Conduction
• Palatine Tonsil/immunology
• Palatine Tonsil/pathology
• Peyer's Patches/immunology
• Peyer's Patches/pathology
• T-Lymphocytes/immunology
• Transcriptome
• Tumor Necrosis Factor-alpha/metabolism
• Tumor Necrosis Factors/genetics
• Tumor Necrosis Factors/metabolism
• Vertebrates

• P20 GM103452 NIGMS NIH HHS
• P30 GM110907 NIGMS NIH HHS

Lymphotoxin-a (LTA) may be associated with the pathogenesis of inflammatory diseases. To assess the association of the LTA rs909253 A/G polymorphism with plasma level and risk of ankylosing spondylitis (AS) in a Chinese Han population. Genotyping and LTA plasma were tested by mass spectroscopy and enzyme-linked immunosorbent assay (ELISA), respectively. The results showed that the average plasma level of LTA in AS was significantly lower than in the controls (P = 0.000). Our results also indicated that LTA rs909253 A/G was associated with a decreased risk of AS (G vs. A: P = 0.014). Significant differences were also found between the rs909253 A/G genotype and down-regulated plasma level in AS patients, compared with controls. After stratification analysis, a decreased risk of AS was associated with the LTA rs909253 G allele (G vs. A) among female patients, younger patients (Yr. < 30), HLA-B27-positive patients. In addition, In conclusion, LTA rs909253 A/G genotype has a significant relationship with decreased susceptibility to AS.

• ankylosing spondylitis
• haplotype
• lta
• polymorphism

• Adolescent
• Adult
• Aged
• Asian People/genetics
• Case-Control Studies
• China
• Female
• Genetic Association Studies
• Genetic Predisposition to Disease
• Genotype
• Humans
• Linkage Disequilibrium
• Lymphotoxin-alpha/genetics
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Spondylitis, Ankylosing/ethnology
• Spondylitis, Ankylosing/genetics
• Young Adult

• Cancer
• Chemotherapy
• Diurnal variability
• Fatigue
• Genes
• Hierarchical linear modeling
• Inflammation

• Autoimmunity
• B cells
• Cancer
• TNF superfamily