Immune cells and interleukins play a crucial role in female-specific pain signaling. Interleukin 16 (IL-16) is a cytokine primarily associated with CD4+ T cell function. While previous studies have demonstrated the important role of spinal CD4+ T cells in neuropathic pain, the specific contribution of IL-16 to neuropathic pain remains unclear. In this study, by using a spinal nerve ligation (SNL)-induced neuropathic pain mice model, we found that SNL induced an increase in IL-16 mRNA levels, which persisted for a longer duration in female mice compared to male mice. Immunofluorescence analysis further confirmed enhanced IL-16- and CD4-positive signals in the spinal dorsal horn following SNL surgery in female mice. Knockdown of spinal IL-16 by siRNA or inhibition of CD4 by FGF22-IN-1, a CD4 inhibitor, attenuated established mechanical and thermal pain hypersensitivity induced by SNL. Furthermore, female mice injected with IL-16 intrathecally exhibited significant spontaneous pain, mechanical and thermal hyperalgesia, all of which could be alleviated by FGF22-IN-1 or a CD3 antibody. Additionally, IL-16 induced astrocyte activation but not microglial activation in the spinal dorsal horn of female mice. Meanwhile, astrocyte activation could be suppressed by the CD3 antibody. These results provide compelling evidence that IL-16 promotes astrocyte activation via CD4 on CD3+ T cells, which is critical for maintaining neuropathic pain in female mice.

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.

OBJECTIVE: Elevated serum interleukin-16 (IL-16) levels have been reported in gastric cancer (GC) tissues; however, the role of IL-16 genotypes in GC susceptibility remains largely unexplored. This study aimed to investigate the contribution of IL-16 genotypes to GC susceptibility and to assess their interactions with smoking, alcohol drinking, and Helicobacter pylori (H. pylori) infection.
METHODS: Polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) methodology was employed to determine IL-16 rs4778889, rs11556218, and rs4072111 genotypic characteristics in 161 patients with GC and 483 controls.
RESULTS: Significant differences were observed in the distribution of genotypic (p=0.0009) and allelic (p=0.0002) frequencies of IL-16 rs11556218 among cases and controls. Specifically, the frequencies of TG and GG genotypes of IL-16 rs11556218 were 37.3% and 6.8% among patients with GC, respectively, which were higher than those among the controls (26.7% and 2.7%). In contrast, no significant differences were found concerning IL-16 rs4778889 or rs4072111. Notably, individuals with IL-16 rs11556218 TT genotypes exhibited significant protective effects against GC when exposed to risk factors, such as smoking, alcohol drinking, and H. pylori infection.
CONCLUSIONS: IL-16 rs11556218 T allele was associated with reduced susceptibility to GC. Furthermore, carriers of the TT genotype showed protection against GC risk factors, including smoking, alcohol drinking, and H. pylori infection. These findings provide valuable insights into the potential role of IL-16 genotypes in GC development and their interactions with lifestyle and infectious factors.

Proinflammatory cytokines are crucial contributors to neuroinflammation in the development of chronic pain. Here, we identified il16, which encodes interleukin-16 (IL-16), as a differentially expressed gene in spinal dorsal horn of a complete Freund\'s Adjuvant (CFA) inflammatory pain model in mice by RNA sequencing. We further investigated whether and how IL-16 regulates pain transmission in the spinal cord and contributes to the development of inflammatory pain hypersensitivity. RNA sequencing and bioinformatics analysis revealed elevated IL-16 transcript levels in the spinal dorsal horn after CFA injection. This increase was further confirmed by qPCR, immunofluorescence, and western blotting. Knockdown of IL-16 by intrathecal injection of IL-16 siRNA not only attenuated CFA-induced mechanical and thermal pain hypersensitivity, but also inhibited enhanced c-fos expression and glial activation in the spinal dorsal horn in male mice injected with CFA. Moreover, exogenous IL-16 induced nociceptive responses and increased c-fos expression and glial activation in spinal dorsal horn. This effect was largely impaired when CD4, the binding receptor for IL-16, was inhibited. In addition, CD4 expression was upregulated in the spinal dorsal horn after CFA injection and CD4 was present in microglia and in contact with astrocytes and activated spinal neurons. Taken together, these results suggest that enhanced IL-16-CD4 signaling triggers pain and activates microglia and astrocytes in the spinal dorsal horn, thus contributing to inflammatory pain. IL-16 may serve as a promising target for the treatment of inflammatory pain.

Hypertensive disorders of pregnancy (HDP) pose a significant risk to maternal and fetal well-being; however, the etiology and pathogenesis of HDP remain ambiguous. It is now widely acknowledged that inflammatory response and the immune system are closely related to HDP. Previous research has identified several inflammatory cytokines are associated with HDP. This study applied Mendelian randomization (MR) analysis to further assess causality.
Patients with HDP who participated in the MR analysis presented with four types of HDP: pre-eclampsia or eclampsia (PE); gestational hypertension (GH); pre-existing hypertension complicating pregnancy, childbirth and the puerperium (EH); and pre-eclampsia or poor fetal growth (PF). A two-sample MR analysis was used to analyze the data in the study. The causal relationship between exposure and outcome was analyzed with inverse variance weighting (IVW), MR Egger, weighted median, weighted mode, and simple mode methods, where IVW was the primary method employed.
Our MR analysis demonstrated a reliable causative effect of Interleukin-9 (IL-9) and macrophage migration inhibitory factor (MIF) on reducing HDP risk, while macrophage inflammatory protein 1-beta (MIP1b), Interleukin-13 (IL-13), and Interleukin-16 (IL-16) were associated with promoting HDP risk.
This study demonstrated that IL-9, MIF, MIP1b, IL-13, and IL-16 may be cytokines associated with the etiology of HDP, and that a number of inflammatory cytokines are probably involved in the progression of HDP. Additionally, our study revealed that these inflammatory cytokines have causal associations with HDP and may likely be potential therapeutic targets for HDP.

Breast cancer is a common cancer type that leads to cancer-related deaths among women. HER2-positive breast cancer, in particular, is associated with poor prognosis due to its high aggressiveness, increased risk of recurrence, and metastasis potential. Previous observational studies have explored potential associations between inflammatory cytokines and the risk of two breast cancer subtypes (HER2-positive and HER2-negative), but the results have been inconsistent. To further elucidate the causal relationship between inflammatory cytokines and the two breast cancer subtypes, we conducted a two-sample Mendelian randomization (MR) study.
We employed a two-sample bidirectional MR analysis using publicly available genome-wide association study (GWAS) statistics. After obtaining instrumental variables, we conducted MR analyses using five different methods to ensure the reliability of our results. Additionally, we performed tests for heterogeneity and horizontal pleiotropy. Subsequently, we conducted a reverse MR study by reversing exposure and outcome variables.
Evidence from our IVW analysis revealed that genetically predicted levels of IL-5 [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.04-1.35, P = 0.012], IL-7 (OR: 1.11, 95% CI: 1.01-1.22, P = 0.037), and IL-16 (OR: 1.13, 95% CI: 1.02-1.25, P = 0.025) were associated with an increased risk of HER2-positive breast cancer. Conversely, IL-10 (OR: 1.14, 95% CI: 1.03-1.26, P = 0.012) was associated with an increased risk of HER2-negative breast cancer. These results showed no evidence of heterogeneity or horizontal pleiotropy (P > 0.05). Results from the reverse MR analysis indicated no potential causal association between breast cancer and inflammatory cytokines (P > 0.05).
Our findings demonstrate that IL-5, IL-7, and IL-16 are risk factors for HER2-positive breast cancer, with varying degrees of increased probability of HER2-positive breast cancer associated with elevated levels of these inflammatory cytokines. Conversely, IL-10 is a risk factor for HER2-negative breast cancer. Reverse studies have confirmed that breast cancer is not a risk factor for elevated levels of inflammatory cytokines. This series of results clarifies the causal relationship between different types of inflammatory cytokines and different subtypes of breast cancer. Based on this research, potential directions for the mechanism research of different inflammatory cytokines and different subtypes of breast cancer have been provided, and potential genetic basis for identifying and treating different subtypes of breast cancer have been suggested.

Takayasu arteritis (TAK) is complicated disorder without reliable biomarkers. Here, we aimed to explore TAK-associated factor panels and their changes after biologic treatment. Five factor panels were identified: 1. systemic inflammation: C3, ESR, CRP, PLT, IL-6, C4, and IgG; 2. vascular inflammation: YKL40, IL-16, PTX3, and CCL2; 3. immune regulation panel: IL-10, IFN-γ, CCL5, and MMP1; 4. angiogenesis and fibrosis: FGF, PDGFAB, and VEGF; and 5. vascular remodeling: CD19+ B cell ratio, MMP3, and leptin. Panel 1 parameters were closely related to disease activity, while Panel 5 parameters, particularly CD19+ B cell ratio and leptin, were significantly higher in ischemic patients. After treatment, tocilizumab had a stronger inhibitory effect on Panel 1 parameters, PTX3, and YKL-40, while adalimumab led to an increase in IL-16, CCL2, and leptin levels. Altogether, these data expanded our knowledge regarding molecular background in TAK development and shed light on precise treatment in future studies.

OBJECTIVE: Periodontitis is a chronic infectious disease, which leads to inflammatory destruction of periodontal supporting tissues. Interleukin 14 (IL-14), Interleukin 16 (IL-16) and serum amyloid A (SAA) have been demonstrated to be abnormally expressed in inflammatory diseases. Therefore, this study was performed to analyzed the expression and potential clinical values of IL-14, 1L-16 and SAA in periodontitis.
METHODS: A total of 100 periodontitis patients and 100 healthy volunteers were recruited and the saliva and serum samples were collected. Then the C-reactive protein (CRP), procalcitonin (PCT), IL-14, 1L-16 and SAA levels in the saliva and serum of periodontitis patients were measured by Elisa kits. Besides, the significance of CRP, PCT, IL-14, 1L-16 and SAA in periodontitis patients were analyzed by receiver operating characteristic (ROC) analysis.
RESULTS: The results showed that CRP, PCT, IL-14, 1L-16 and SAA levels were significantly increased in the the saliva and serum of the periodontitis patients. Additionally, the area under the curve (AUC) of saliva CRP, PCT, IL-14, 1L-16 and SAA for the diagnosis of periodontitis were 0.9035, 0.9435, 0.9508, 0.9500 and 0.9467, respectively. The AUC of serum CRP, PCT, IL-14, 1L-16 and SAA for the diagnosis of periodontitis were 0.9035, 0.9435, 0.9508, 0.9500 and 0.9467, respectively. What\'s more, the diagnostic value of IL-14, 1L-16 and SAA were enhanced when combining with CRP and PCT.
CONCLUSIONS: This study demonstrated that IL-14, IL-16 and SAA expressions were upregulated in periodontitis patients and exhibited a significant significance for periodontitis diagnosis.

Cardiac surgery can provoke an acute cytokine storm that may contribute to the development of postoperative multiple organ dysfunction syndrome. We prospectively observed patients undergoing cardiac surgery and divided them into two groups: the severe group and the mild group. Healthy individuals were enrolled acting as the control group for comparison. Plasma samples and clinical data were recorded at the initiation of cardiac-pulmonary bypass (CPB) and 3, 6, 12, 24, and 48 h after initiation of CPB. Cytokine levels were detected using the Luminex® technique. Thirty-nine adults were enrolled in this study (14 in the severe group, 15 in the mild group, and 10 in the control group). Cytokine concentrations were significantly higher in the severe group. Principal component analysis was used to establish a cytokine storm intensity curve, which represented the overall trend of 10 cytokines. The peak concentrations of interleukin (IL)-6, IL-10, and IL-16 were 425.1, 198.5, and 623.0 pg/mL, which were more than 1,200, 1,800, and 240 times the normal level, respectively. The maximum cytokine storm intensity predated the maximum Vasoactive-Inotropic Score (VIS) and Sequential Organ Failure Assessment (SOFA) score in the severe group. Cytokine storm response to cardiac surgery occurred early and was associated with disease severity. Interventions to cytokine storm should be initiated early as guided by cytokine storm biomarkers such as IL-6, IL-10, and IL-16 in severe patients undergoing cardiac surgery. Clinical Trial Registration: ChiCTR1900021351.