The systemic administration of interleukin-16 (IL-16, 3-30 ng/kg) induced thermal hyperalgesia in mice, that was prevented by the acute injection of an anti-CD4 antibody (1 µg/kg), the depletion of circulating white blood cells by cyclophosphamide or the specific reduction of circulating CD4+ cells provoked by a high dose of an anti-CD4 antibody (30 µg/mouse, 24 h before). IL-16-induced hyperalgesia was locally inhibited after intraplantar (i.pl.) administration of the non-selective cyclooxygenase (COX) inhibitor diclofenac, the COX-1 inhibitor SC-560, the COX-2 inhibitor celecoxib, the TRPV1 antagonist capsazepine or the TRPA1 antagonist HC030031, thus demonstrating that prostaglandins and TRP channels are involved in this effect. The i.pl. administration of low doses of IL-16 (0.1-1 ng) evoked local hyperalgesia suggesting the possibility that IL-16 could participate in hypernociception associated to local tissue injury. Accordingly, IL-16 concentration measured by ELISA was increased in paws acutely inflamed with carrageenan or chronically inflamed with complete Freund´s adjuvant (CFA). This augmentation was reduced after white cell depletion with cyclophosphamide or neutrophil depletion with an anti-Ly6G antibody. Immunofluorescence and flow cytometry experiments showed that the increased concentration of IL-16 levels found in acutely inflamed paws is mainly related to the infiltration of IL-16+ neutrophils, although a reduced number of IL-16+ lymphocytes was also detected in paws inflamed with CFA. Supporting the functional role of IL-16 in inflammatory hypernociception, the administration of an anti-IL-16 antibody dose-dependently reduced carrageenan- and CFA-induced thermal hyperalgesia and mechanical allodynia. The interest of IL-16 as a target to counteract inflammatory pain is suggested.

UNASSIGNED: Obesity is a chronic condition associated with low-grade inflammation mainly due to immune cell infiltration of white adipose tissue (WAT). WAT is distributed into two main depots: subcutaneous WAT (sWAT) and visceral WAT (vWAT), each with different biochemical features and metabolic roles. Proinflammatory cytokines including interleukin (IL)-16 are secreted by both adipocytes and infiltrated immune cells to upregulate inflammation. IL-16 has been widely studied in the peripheral proinflammatory immune response; however, little is known about its role in adipocytes in the context of obesity.
UNASSIGNED: We aimed to study the levels of IL-16 in WAT derived from sWAT and vWAT depots of humans with obesity and the role of this cytokine in palmitate-exposed 3T3-L1 adipocytes.
UNASSIGNED: The results demonstrated that IL-16 expression was higher in vWAT compared with sWAT in individuals with obesity. In addition, IL-16 serum levels were higher in patients with obesity compared with normal-weight individuals, increased at 6 months after bariatric surgery, and at 12 months after surgery decreased to levels similar to before the intervention. Our in vitro models showed that IL-16 could modulate markers of adipogenesis (Pref1), lipid metabolism (Plin1, Cd36, and Glut4), fibrosis (Hif1a, Col4a, Col6a, and Vegf), and inflammatory signaling (IL6) during adipogenesis and in mature adipocytes. In addition, lipid accumulation and glycerol release assays suggested lipolysis alteration.
UNASSIGNED: Our results suggest a potential role of IL-16 in adipogenesis, lipid and glucose homeostasis, fibrosis, and inflammation in an obesity context.

Endometriosis, affecting 6%-10% of women, often leads to pain and infertility and its underlying inflammatory mechanisms are poorly understood. We established endometriosis models in wild-type and IL16KO mice, revealing the driver function of IL-16 in initiating endometriosis-related inflammation. Using an in vitro system, we confirmed iron overload-induced GSDME-mediated pyroptosis as a key trigger for IL-16 activation and release. In addition, our research led to the development of Z30702029, a compound inhibiting GSDME-NTD-mediated pyroptosis, which shows promise as a therapeutic intervention for endometriosis. Importantly, our findings extend beyond endometriosis, highlighting GSDME-mediated pyroptosis as a broader pathway for IL-16 release and offering insights into potential treatments for various inflammatory conditions.

The discovery of promising cytokines and clarification of their immunological mechanisms in controlling the intracellular fate of Mycobacterium tuberculosis (Mtb) are necessary to identify effective diagnostic biomarkers and therapeutic targets. To escape immune clearance, Mtb can manipulate and inhibit the normal host process of phagosome maturation. Phagosome maturation arrest by Mtb involves multiple effectors and much remains unknown about this important aspect of Mtb pathogenesis. In this study, we found that interleukin 16 (IL-16) is elevated in the serum samples of Tuberculosis (TB) patients and can serve as a specific target for treatment TB. There was a significant difference in IL-16 levels among active TB, latent TB infection (LTBI), and non-TB patients. This study first revealed that macrophages are the major source of IL-16 production in response to Mtb infection, and elucidated that IL-16 can promote Mtb intracellular survival by inhibiting phagosome maturation and suppressing the expression of Rev-erbα which can inhibit IL-10 secretion. The experiments using zebrafish larvae infected with M. marinum and mice challenged with H37Rv demonstrated that reducing IL-16 levels resulted in less severe pathology and improved survival, respectively. In conclusion, this study provided direct evidence that Mtb hijacks the host macrophages-derived interleukin 16 to enhance intracellular growth. It is suggesting the immunosuppressive role of IL-16 during Mtb infection, supporting IL-16 as a promising therapeutic target.

UNASSIGNED: This study evaluated the change in IL-16 levels in patients with high-grade glial tumors undergoing radiotherapy (RT) and healthy individuals (control group).
UNASSIGNED: Serum IL-16 levels of 35 high-grade glioma patients receiving radiotherapy (RT) and 30 healthy individuals were compared. We compared the IL-16 levels before (RT0) and after the (RT1) and IL-16 levels were measured and the relationship of this change with other characteristics such as age, gender, weight, height, and blood test results.
UNASSIGNED: The RT0-IL-16 level was approximately 15 pg/ml higher than the RT1 measurement in the patient group. The mean RT0-IL-16 levels in the patient group were approximately 10 pg/ml higher than the mean IL-16 levels in the control group. Likewise, at the RT1 time-point, the mean IL-16 levels for the patient group were approximately 5 pg/ml lower than the mean IL-16 for the control group. The mean RT0-RT1-IL-16 value tended to be higher in female patients than in male patients.
UNASSIGNED: The application of RT reduces the overall IL-16 levels, suggesting the efficacy of RT, as well as the role of IL-16 in tumorigenesis.

Epidemiological studies of older adults have suggested a differential sex-specific prevalence of sarcopenia, which is a condition characterized by a progressive loss of skeletal muscle mass and function. Recently, we collected serum samples from 80 fully evaluated older adults and identified CXCL12α as a sex-independent serum marker of sarcopenia. Here, we used this serum collection to find potential sex-specific serum markers via the simultaneous quantification of 34 inflammatory cytokines/chemokines. The appendicular skeletal muscle index (ASMI) was used as a decisive criterion for diagnosing sarcopenia. A Pearson correlation analysis revealed a negative correlation between ASMI and serum IL-16 in females only (p = 0.021). Moreover, women with sarcopenia exhibited significantly higher IL-16 (p = 0.025) serum levels than women in a control group. In contrast, males with sarcopenia had lower IL-16 (p = 0.013) levels than males in a control group. The further use of Fisher\'s exact test identified obesity (p = 0.027) and high serum levels of IL-16 (p = 0.029) as significant risk factors for sarcopenia in females. In male older adults, however, malnutrition (p = 0.028) and low serum levels of IL-16 (p = 0.031) were the most significant risk factors for sarcopenia. The differential sex-specific associations of IL-16 in older adults may contribute to the development of more precise regression models for future research and elucidate the role of IL-16 in the progression of sarcopenic obesity.

Proteins containing PDZ (post-synaptic density, PSD-95/disc large, Dlg/zonula occludens, ZO-1) domains assemble signaling complexes that orchestrate cell responses. Viral pathogens target host PDZ proteins by coding proteins containing a PDZ-binding motif (PBM). The presence of a PBM in the SARS-CoV-2 E protein contributes to the virus\'s pathogenicity. SARS-CoV-2 infects epithelia, but also cells from the innate immune response, including monocytes and alveolar macrophages. This process is critical for alterations of the immune response that are related to the deaths caused by SARS-CoV-2. Identification of E-protein targets in immune cells might offer clues to understanding how SARS-CoV-2 alters the immune response. We analyzed the interactome of the SARS-CoV-2 E protein in human monocytes. The E protein was expressed fused to a GFP tag at the amino terminal in THP-1 monocytes, and associated proteins were identified using a proteomic approach. The E-protein interactome provided 372 partners; only 8 of these harbored PDZ domains, including the cell polarity protein ZO-2, the chemoattractant IL-16, and syntenin. We addressed the expression and localization of the identified PDZ proteins along the differentiation of primary and THP-1 monocytes towards macrophages and dendritic cells. Our data highlight the importance of identifying the functions of PDZ proteins in the maintenance of immune fitness and the viral alteration of inflammatory response.

UNASSIGNED: Given the increasing prevalence of wildfires worldwide, understanding the effects of wildfire air pollutants on human health-particularly in specific immunologic pathways-is crucial. Exposure to air pollutants is associated with cardiorespiratory disease; however, immune and epithelial barrier alterations require further investigation.
UNASSIGNED: We sought to determine the impact of wildfire smoke exposure on the immune system and epithelial barriers by using proteomics and immune cell phenotyping.
UNASSIGNED: A San Francisco Bay area cohort (n = 15; age 30 ± 10 years) provided blood samples before (October 2019 to March 2020; air quality index = 37) and during (August 2020; air quality index = 80) a major wildfire. Exposure samples were collected 11 days (range, 10-12 days) after continuous exposure to wildfire smoke. We determined alterations in 506 proteins, including zonulin family peptide (ZFP); immune cell phenotypes by cytometry by time of flight (CyTOF); and their interrelationship using a correlation matrix.
UNASSIGNED: Targeted proteomic analyses (n = 15) revealed a decrease of spondin-2 and an increase of granzymes A, B, and H, killer cell immunoglobulin-like receptor 3DL1, IL-16, nibrin, poly(ADP-ribose) polymerase 1, C1q TNF-related protein, fibroblast growth factor 19, and von Willebrand factor after 11 days\' average continuous exposure to smoke from a large wildfire (P < .05). We also observed a large correlation cluster between immune regulation pathways (IL-16, granzymes A, B, and H, and killer cell immunoglobulin-like receptor 3DL1), DNA repair [poly(ADP-ribose) 1, nibrin], and natural killer cells. We did not observe changes in ZFP levels suggesting a change in epithelial barriers. However, ZFP was associated with immune cell phenotypes (naive CD4+, TH2 cells).
UNASSIGNED: We observed functional changes in critical immune cells and their proteins during wildfire smoke exposure. Future studies in larger cohorts or in firefighters exposed to wildfire smoke should further assess immune changes and intervention targets.

OBJECTIVE: To determine whether the maternal plasma concentrations of cytokines are higher in pregnant women with postpartum hemorrhage (PPH) compared to pregnant women without PPH.
METHODS: A retrospective case-control study included 36 women with PPH and 72 matched controls. Cases and controls were matched for gestational age at delivery, labor status, delivery route, parity, and year of sample collection. Maternal plasma samples were collected up to 3 days prior to delivery. Comparison of the plasma concentrations of 29 cytokines was performed by using linear mixed-effects models and included adjustment for covariates and multiple testing. A false discovery rate adjusted p-value <0.1 was used to infer significance. Random forest models with evaluation by leave-one-out and 9-fold cross-validation were used to assess the combined value of the proteins in predicting PPH.
RESULTS: Concentrations of interleukin (IL)-16, IL-6, IL-12/IL-23p40, monocyte chemotactic protein 1 (MCP-1), and IL-1β were significantly higher in PPH than in the control group. This difference remained significant after adjustment for maternal age, clinical chorioamnionitis, and preeclampsia. Multi-protein random forest proteomics models had moderate cross-validated accuracy for prediction of PPH [area under the ROC curve, 0.69 (0.58-0.81) by leave-one-out cross validation and 0.73 (0.65-0.81) by 9-fold cross-validation], and the inclusion of clinical and demographic information did not increase the prediction performance.
CONCLUSIONS: Pregnant women with severe PPH had higher median maternal plasma concentrations of IL-16, IL-6, IL-12/IL-23p40, MCP-1, and IL-1β than patients without PPH. These cytokines could serve as biomarkers or their pathways may be therapeutic targets.

BACKGROUND: /objectives. Single nucleotide polymorphisms (SNPs) located at the 3\'-UTR region of the target genes of microRNAs (miRNAs) can dysregulate their expression via disrupting the binding site of miRNAs. Interleukin-16 (IL-16) is involved in the pathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In the current study, we assessed the possible association between rs1131445 polymorphism in IL-16 gene with risk and clinical characteristics of RA and SLE in the Iranian population.
METHODS: In this case-control study, 120 patients with RA, 120 patients with SLE, and 120 unrelated healthy subjects were collected to estimate rs1131445 (T > C) polymorphism in IL-16 gene using real-time PCR high-resolution melting (HRM) method.
RESULTS: Our results demonstrated considerable associations between TC genotype and C allele of rs1131445 with enhanced risk of RA (ORfor TC genotype = 3.01; 95%CI [1.667-5.526], P < 0.001; ORfor C allele = 1.96; 95%CI [1.314-2.941], P < 0.001). Besides, there was a marginal association between CC genotype and increased risk of RA (P: 0.031). However, there was an insignificant correlation between genotypes and allele frequencies of rs1131445 with incidence risk of SLE (P > 0.05). Moreover, stratification analysis indicated that the C allele in rs1131445 was linked with disease activity-associated laboratory parameters such as CRP and ESR in both RA and SLE patients, as well as the higher incidence of neurological symptoms in SLE subjects (P < 0.05).
CONCLUSIONS: These results proposed a significant association between IL-16 polymorphism and augmented risk of RA and clinical characteristics of RA and SLE.