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PurposeBlood flow restricted resistance exercise (BFR-RE) is an emerging hypertrophy training modality. A complete profile of its mechanisms of action has yet to be elucidated. Cytokines are universal intercellular messengers. Recent research has implicated certain cytokines (termed “myokines”) in skeletal muscle hypertrophy pathways; however, little research has been conducted on the systemic myokine response to BFR-RE as potential hypertrophic biomarkers. Therefore, this project was conducted to determine any differences in the systemic myokine response between BFR-RE and control conditions.MethodsThe appearance of systemic myokines interleukin-6 (IL-6), interleukin-15 (IL-15), and decorin were measured following acute bouts of low-load resistance exercise, BFR-RE, and high-load resistance exercise in physically active young males to determine if BFR-RE modifies the exercise-induced systemic myokine response.ResultsNo measurable levels of IL-6 were observed during the project. No significant effects were observed for IL-15. A significant time (11.91% increase pre to post exercise; p < 0.05) but no condition or condition by time effect was observed for decorin.ConclusionThese findings suggest that BFR-RE does not modify the systemic myokine appearance of IL-6, IL-15, or decorin when compared to control conditions.

Increased serum levels of IL-15 are reported in type 1 diabetes (T1D). Here we report elevated serum soluble IL-15Rα levels in human T1D. To investigate the role of IL-15/IL-15Rα in the pathogenesis of T1D, we generated double transgenic mice with pancreatic β-cell expression of IL-15 and IL-15Rα. The mice developed hyperglycemia, marked mononuclear cell infiltration, β-cell destruction, and anti-insulin autoantibodies that mimic early human T1D. The diabetes in this model was reversed by inhibiting IL-15 signaling with anti-IL2/IL15Rβ (anti-CD122), which blocks IL-15 transpresentation. Furthermore, the diabetes could be reversed by administration of the Janus kinase 2/3 inhibitor tofacitinib, which blocks IL-15 signaling. In an alternative diabetes model, nonobese diabetic mice, IL15/IL-15Rα expression was increased in islet cells in the prediabetic stage, and inhibition of IL-15 signaling with anti-CD122 at the prediabetic stage delayed diabetes development. In support of the view that these observations reflect the conditions in humans, we demonstrated pancreatic islet expression of both IL-15 and IL-15Rα in human T1D. Taken together our data suggest that disordered IL-15 and IL-15Rα may be involved in T1D pathogenesis and the IL-15/IL15Rα system and its signaling pathway may be rational therapeutic targets for early T1D.

Interleukin-15 (IL-15) is a pro-inflammatory cytokine which signals via a specific alpha receptor subunit (IL-15Rα). Increased IL-15 level has been observed in cardiovascular patients and IL-15 immunoreactivity has been detected at vulnerable atherosclerotic plaques. Due to the association between adipose tissue distribution, inflammation and coronary artery disease (CAD), we quantified IL-15 and IL-15Rα in CAD patients with different adiposity and adipose tissue distribution and we evaluated whether epicardial adipose tissue (EAT), a visceral fat depot surrounding and infiltrating myocardium, may be a source of both molecules. IL-15 and IL-15Rα proteins were quantified by enzyme-linked immunosorbent assays. Gene expression of IL-15 and IL-15Rα in EAT depots was evaluated by one colour microarray platform. EAT thickness was measured by echocardiography. Plasmatic IL-15 and IL-15Rα levels were higher in CAD than non-CAD patients. After classification according to adipose tissue distribution, IL-15 was higher in CAD patients with increased abdominal adiposity. Increased level of IL-15Rα was observed both in CAD and non-CAD patients with increased abdominal fat. EAT was a source of IL-15 and IL-15Rα and their expression was higher in CAD patients with increased EAT thickness. In conclusion, our data suggest that circulating levels of IL-15 and IL-15Rα seem to reflect visceral distribution of adipose tissue and that EAT may be a potential source of both IL-15 and IL-15Rα. Future studies on the relationship between IL-15, visceral fat and characteristics of atherosclerotic plaques could help to better understand the complex biology of this cytokine.

Interleukin-15 (IL-15) is a pleotrophic cytokine that is involved in the pathogenesis of diverse inflammatory rheumatic diseases. The aims of this study were to compare serum IL-15 levels and expression of its receptor (IL-15Rα) in Behçet’s disease (BD) with those in other rheumatic diseases and to identify the relationship between serum IL-15 levels and various clinical parameters in BD. One hundred fifty-eight subjects consisting of 40 BD, 38 systemic lupus erythematosus (SLE), 40 rheumatoid arthritis (RA), and 40 healthy controls were enrolled. Serum IL-15 levels were measured using an enzyme-linked immunosorbent assay. The proportion of IL-15Rα expression on each leukocyte subset was measured by flow cytometry. Erythrocyte sediment rate (ESR) and C-reactive protein (CRP) were measured for each enrolled subject. The clinical activity index of BD was assessed for BD patients. Serum IL-15 levels in BD patients are significantly higher than those of healthy controls, SLE, and RA patients ( p  < 0.001, p  < 0.001, and p  < 0.001, respectively). Serum IL-15 levels in BD were closely related to ESR ( r  = 0.405, p  = 0.027), but not to CRP or the clinical activity index of BD ( p  > 0.05 for both). Additionally, there was no difference in serum IL-15 levels between active and inactive disease states in BD ( p  > 0.05). The proportion of IL-15Rα expression on total leukocytes was much lower for all rheumatic diseases, including BD, than in healthy controls ( p  < 0.01 for SLE, p  < 0.01 for RA, and p  < 0.05 for BD). IL-15 and IL-15Rα system may be involved in the inflammatory process and pathogenesis of BD.

The purpose of this study is to evaluate the demographics, clinical presentation, laboratory findings, and gastrointestinal endoscopic findings in children with CD and assess their relationship with interleukin-15 (IL-15) single-nucleotide polymorphism (SNP) (rs2857261) and serum IL-15 levels. This case–control and prospective cohort study included 54 newly diagnosed pediatric CD patients attending the Gastroenterology Clinic at Alexandria University Children’s Hospital and 44 age- and sex-matched healthy controls. Demographics, clinical data, laboratory tests, Marsh classification, and IL-15 SNP (rs2857261) genotypes were analyzed. Follow-up after 9 months on a gluten-free diet (GFD) was conducted. The mean age of patients and controls was 8.62 ± 4.4 and 8.07 ± 4.7 years, respectively, with no significant difference ( p  = 0.55). Male representation was 48.1% in patients and 47.7% in controls ( p  = 0.97). The most common presenting symptoms in CD patients were abdominal distension (61.11%) and failure to thrive (59.26%). Laboratory findings showed that mean anti-tissue transglutaminase immunoglobulin A was 103 ± 168 U/ml, and anti-endomysium immunoglobulin A was positive in 51.85% of patients. Histopathological assessment revealed Marsh 3C as the most common finding (37%), while 37% of patients were diagnosed without biopsy. IL-15 SNP (rs2857261) analysis showed a significantly higher prevalence of the A/A genotype in CD patients compared to controls ( p  < 0.0001). The A/G and G/G genotypes were protective against CD, with odds ratios of 0.088 and 0.079, respectively. No significant associations were observed between IL-15 genotypes and clinical, laboratory, or histological variables. After 6 to 9 months on a GFD, genotype did not significantly influence symptom resolution ( p  > 0.05). Conclusions : Serum IL-15 levels are elevated in newly diagnosed pediatric CD patients. The IL-15 SNP (rs2857261) A/A genotype is associated with increased susceptibility to CD, while the A/G and G/G genotypes appear protective. These findings highlight IL-15 as a potential biomarker and therapeutic target in CD. Further large-scale studies are warranted to validate these findings and explore therapeutic applications. What is Known: • Celiac disease is an immune-mediated enteropathy linked to HLA-DQ2/DQ8 alleles, with IL-15 playing a key role in its pathogenesis. • Variability in IL-15 genetic polymorphisms has been suggested but remains underexplored in pediatric populations. What is New: • This study identifies the IL-15 SNP (rs2857261) A/A genotype as a risk factor for CD, while A/G and G/G genotypes are protective. • Elevated serum IL-15 levels in newly diagnosed patients highlight its potential as a biomarker and therapeutic target.

Cervical tuberculous lymphadenitis (CTL) represents a localized manifestation of infection in which immune responses are organized within lymphoid tissue. While cytotoxic lymphocyte responses contribute to antimycobacterial immunity, the cytokine networks coordinating these responses in human lymph node tuberculosis remain incompletely defined. We performed integrated immune profiling of patients with CTL (n = 60) and non-tuberculous cervical lymphadenopathy (CNTL; n = 44). Immune-gene expression was quantified in peripheral blood and lymph node mononuclear cells by qPCR. Systems-level analyses including principal component and correlation-network approaches were used to define coordinated immune pathways. Serum IL-15 was measured by ELISA, and tissue localization of IL-15 and IL-15Rα was examined by immunohistochemistry. CTL was characterized by a structured cytotoxic immune program enriched for granulysin, granzyme B, perforin, IFN-γ, and CCL5. Network analysis identified IL-15 as a highly connected hub within this cytotoxic module in CTL. IL-15 transcripts were significantly elevated in both blood and lymph node compartments (p = 0.0003; p = 0.0007, respectively) and strongly correlated with cytotoxic effector genes. Circulating IL-15 concentrations were higher in CTL than CNTL (p < 0.0001) and increased with GeneXpert-defined bacillary burden (AUC 0.73). Immunohistochemistry demonstrated IL-15 and IL-15Rα expression within CD68 macrophages localized to granulomatous regions, consistent with macrophage-mediated IL-15 trans-presentation within sites of infection. These findings identify IL-15 as a potential central organizer of cytotoxic immune pathways in CTL and highlight IL-15-linked immune signatures as biologically informative features of CTL immunopathogenesis.

We generated a novel mouse strain expressing transgenic human interleukin-15 (IL-15) using the severe immunodeficient NOD/Shi- scid -IL-2Rγ null (NOG) mouse genetic background (NOG-IL-15 Tg). Human natural killer (NK) cells, purified from the peripheral blood (hu-PB-NK) of normal healthy donors, proliferated when transferred into NOG-IL-15 Tg mice. In addition, the cell number increased, and the hu-PB-NK cells persisted for 3 months without signs of xenogeneic graft versus host diseases (xGVHD). These in vivo -expanded hu-PB-NK cells maintained the original expression patterns of various surface antigens, including NK receptors and killer cell immunoglobulin-like receptor (KIR) molecules. They also contained significant amounts of granzyme A and perforin. Inoculation of K562 leukemia cells into hu-PB-NK-transplanted NOG-IL-15 Tg mice resulted in significant suppression of tumor growth compared with non-transplanted mice. Furthermore, NOG-IL-15 Tg mice allowed for engraftment of in vitro -expanded NK cells prepared for clinical cell therapy. These cells exerted antibody-dependent cell-mediated cytotoxicity (ADCC) on Her2-positive gastric cancer cells in the presence of therapeutic anti-Her2 antibody, and subsequently suppressed tumor growth. Our results collectively suggest that the NOG-IL-15 Tg mice are a useful model for studying human NK biology and evaluating human NK cell-mediated in vivo cytotoxicity.

Hypobaric hypoxia (HH) limits oxygen supply to tissues and increases metabolic demands, especially during exercise. We studied the influence of HH exposure on the subcutaneous adipose tissue (SAT) thickness and circulating metabolic-related cytokines levels after a resistance training (RT) program. Twenty trained men participated in a traditional hypertrophy RT for 8 weeks (three sessions/week) under intermittent terrestrial HH (2320 m) or normoxia (N, 690 m) conditions. Before, at week 6, and after the RT, SAT, and vastus lateralis (VL) muscle thickness were measured by ultrasound. Blood samples were taken to analyse serum cytokines (IL-6, IL-15, irisin, and myostatin) by multiplex immunoassay. Our findings revealed a moderate reduction in IL-6 and irisin in HH following the RT (ES < −0.64; p < 0.05). Additionally, RT in HH promoted serum IL-15 release (ES = 0.890; p = 0.062), which exhibited a trivial inverse association with the reductions observed on SAT (−17.69%; p < 0.001) compared with N. RT in HH explained ~50% of SAT variance (p < 0.001). These results highlight the benefit of stressor factors linked to RT in HH on SAT through the modulation of serum metabolic cytokine profiles, suggesting a potential effect on overall body composition.

IL-15 has been postulated to play an important role in HIV-1 infection, yet there are conflicting reports regarding its expression levels in these patients. We sought to measure the level of IL-15 in a large, well characterised cohort of HIV-1 infected patients and correlate this with well known markers of inflammation, including CRP, D-dimer, sCD163 and sCD14. IL-15 levels were measured in 501 people (460 patients with HIV-1 infection and 41 uninfected controls). The HIV-1 infected patients were divided into 4 groups based on viral load: <50 copies/ml, 51-10,000 copies/ml, 10,001-100,000 copies/ml and >100,000 copies/ml. The Mann Whitney test (non-parametric) was used to identify significant relationships between different patient groups. IL-15 levels were significantly higher in patients with viral loads >100,000 copies/ml (3.02 ± 1.53 pg/ml) compared to both uninfected controls (1.69 ± 0.37 pg/ml, p<0.001) or patients with a viral load <50 copies/ml (1.59 ± 0.40 pg/ml (p<0.001). There was a significant correlation between HIV-1 viremia and IL-15 levels (Spearman r = 0.54, p<0.001) and between CD4+ T cell counts and IL-15 levels (Spearman r = -0.56, p<0.001). IL-15 levels are significantly elevated in HIV-1 infected patients with viral loads >100,000 copies/ml compared to uninfected controls, with a significant direct correlation noted between IL-15 and HIV-1 viremia and an inverse correlation between IL-15 levels and CD4+ T cell counts. These data support a potential role for IL-15 in the pathogenesis of HIV-associated immune activation.