Interleukin-27 Regulates Adaptative Immune Responses Associated With Control of Parasite Replication in Canine Leishmaniasis.

Interleukin 27 (IL-27) is a cytokine that regulates susceptibility to Leishmania infantum infection in humans and experimental models. This cytokine has not yet been described in canine leishmaniasis (CanL). Therefore, we investigated whether IL-27 has a regulatory role in CanL. The EBI3 and p28 subunits of IL-27 were measured in splenic leukocytes culture supernatant from dogs with CanL and compared to control dogs. We also correlated EBI3 and p28 levels with IL-21, anti-L. infantum antibodies and parasite loads. We performed functional assays followed by IL-27 blockade and measured parasite loads, production of cytokines in splenic leukocytes culture supernatant, and the expression of PD-1, CTLA-4, phospho-Stat-1/3, T-bet, GATA3 and nitric oxide production (NO). Both IL-27 subunits increased in the supernatant of dogs with CanL compared to control dogs. EBI3 and p28 levels showed a moderate positive correlation with IL-21 (r = 0.67, p < 0.0001 and r = 0.45, p < 0.012, respectively), and the EBI3 subunit was positively associated with anti-L. infantum IgG antibodies (r = 0.38, p < 0.040) and parasite load (r = 0.47, p < 0.009). IL-27 and IL-21 participate of immune responses in CanL. IL-27 may be associated with the failure of immunity to control parasite replication via upregulation of the expression of PD-1, CTLA-4, T-bet and NO in splenic leukocytes from dogs with CanL. These findings suggest that the pathways regulated by IL-27 are involved in CanL pathogenesis in the host, and may be targets for new therapies.

Interleukin signaling in the regulation of natural killer cells biology in breast cancer.

In the field of breast cancer treatment, the immunotherapy involving natural killer (NK) cells is increasingly highlighting its distinct potential and significance. Members of the interleukin (IL) family play pivotal regulatory roles in the growth, differentiation, survival, and apoptosis of NK cells, and are central to their anti-tumor activity. These cytokines enhance the ability of NK cells to recognize and eliminate tumor cells by binding to specific receptors and activating downstream signaling pathways. Furthermore, interleukins do not function in isolation; the synergistic or antagonistic interactions between different interleukins can drive NK cells toward various functional pathways, ultimately leading to diverse outcomes for breast cancer patients. This paper reviews the intricate relationship between NK cells and interleukins, particularly within the breast cancer tumor microenvironment. Additionally, we summarize the latest clinical studies and advancements in NK cell therapy for breast cancer, along with the potential applications of interleukin signaling in these therapies. In conclusion, this article underscores the critical role of NK cells and interleukin signaling in breast cancer treatment, providing valuable insights and a significant reference for future research and clinical practice.

Analysis of B cell proliferation in response to in vitro stimulation in patients with CVID.

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by defective antibody production and impaired differentiation of B cells. B cell proliferation is an essential step for antibody synthesis. Depending on the nature of the stimulus, their response may be either T-cell-dependent or T-cell-independent. METHODS: We studied 23 CVID patients and 14 healthy donors (HD). The patients were categorized based on their percentage of memory B cells. In addition to standard immunophenotyping of circulating human B and T cell subsets, an in vitro CFSE dilution assay was used to assess the proliferative capacity of B cells and to compare the activation of the T cell-dependent and T cell-independent response among the patients. RESULTS: Patients with a reduction in memory B cells exhibited an increase in follicular T cells (Tfh) and showed low proliferation in response to PKW, CpG, and SAC stimuli (Condition II) (p= 0.0073). In contrast, patients with a normal percentage of memory B cells showed a high expression of IL-21R and low proliferation in response to CPG (Condition III); IL-21, CD40L, and anti-IgM (Condition IV) stimuli (p= 0.0163 and p = 0.0475, respectively). CONCLUSION: Defective proliferation in patients depends on the type of stimulus used and the phenotypic characteristics of the patients. Further studies are necessary to understand the disease mechanisms, which may guide us toward identifying genetic defects associated with CVID.

Sirtuin 6 inhibits group 3 innate lymphoid cell function and gut immunity by suppressing IL-22 production.

Introduction: Group 3 innate lymphoid cells (ILC3s) are enriched in the intestinal mucosa and play important roles in host defense against infection and inflammatory diseases. Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD+)- dependent deacetylase and has been shown to control intestinal epithelial cell differentiation and survival. However, the role of SIRT6 in ILC3s remains unknown. Methods: To investigate the role of SIRT6 in gut ILC3s, we generated SIRT6 conditional knockout mice by crossing Rorccre and Sirt6flox/flox mice. Cell number and cytokine production was examined using flow cytometry. Citrobacter rodentium infection and dextran sodium sulfate-induced colitis models were used to determine the role of SIRT6 in gut defense. RT-qPCR, flow cytometry and immunohistochemistry were used to assess the intestinal inflammatory responses. Results: Here we show that SIRT6 inhibits IL-22 expression in intestinal ILC3s in a cell-intrinsic manner. Deletion of SIRT6 in ILC3s does not affect the cell numbers of total ILC3s and subsets, but results in increased IL-22 production. Furthermore, ablation of SIRT6 in ILC3s protects mice against Citrobacter rodentium infection and dextran sodium sulfate-induced colitis. Our results suggest that SIRT6 may play a role in ILC3 function by regulating gut immune responses against bacterial infection and inflammation. Discussion: Our finding provided insight into the relation of epigenetic regulators with IL-22 production and supplied a new perspective for a potential strategy against inflammatory bowel disease.

Antiviral activity of bovine type III interferon against bovine viral diarrhea virus is greatly reduced in bovine turbinate cells due to limited expression of IFN lambda receptor 1 (IL-28Rα).

Introduction: The antiviral activity of recombinant bovine interferon lambda 3 (bovIFN-λ3) against bovine viral diarrhea virus (BVDV) has been demonstrated in vitro in Madin-Darby bovine kidney cells (MDBK) and in vivo in cattle. However, anti-BVDV activity of bovIFN-λ3 has not been studied in bovine respiratory tract epithelial cells, supposedly a primary target of BVDV infection when entering the host by the oronasal route. Methods: Here we investigated the anti-BVDV activity of bovIFN-λ3 in bovine turbinate-derived primary epithelial cells (BTu) using BVDV infection and immunoperoxidase staining, TCID50, RT-qPCR, DNA and transcriptome sequencing, and transfection with plasmids containing the two subunits, IL-28Rα and IL-10Rß that constitute the bovIFN-λ3 receptor. Results: Our immunoperoxidase staining, RT-qPCR, and TCID50 results show that while BVDV was successfully cleared in MDBK cells treated with bovIFN-λ3 and bovIFN-α, only the latter, bovIFN-α, cleared BVDV in BTu cells. Preincubation of MDBK cells with bovIFN-λ3 before BVDV infection was needed to induce optimal antiviral state. Both cell types displayed intact type I and III IFN signaling pathways and expressed similar levels of IL-10Rß subunit of the type III IFN receptor. Sequencing of PCR amplicon of the IL-28Rα subunit revealed intact transmembrane domain and lack of single nucleotide polymorphisms (SNPs) in BTu cells. However, RT-qPCR and transcriptomic analyses showed a lower expression of IL-28Rα transcripts in BTu cells as compared to MDBK cells. Interestingly, transfection of BTu cells with a plasmid encoding IL-28Rα subunit, but not IL-10Rß subunit, established the bovIFN-λ3 sensitivity showing similar anti-BVDV activity to the response in MDBK cells. Conclusion: Our results demonstrate that the sensitivity of cells to bovIFN-λ3 depends not only on the quality but also of the quantity of the IL-28Rα subunit of the heterodimeric receptor. A reduction in IL-28Rα transcript expression was detected in BTu as compared to MDBK cells, despite the absence of spliced variants or SNPs. The establishment of bovIFN-λ3 induced anti-BVDV activity in BTu cells transfected with an IL-28Rα plasmid suggests that the level of expression of this receptor subunit is crucial for the specific antiviral activity of type III IFN in these cells.

Interleukin-34-orchestrated tumor-associated macrophage reprogramming is required for tumor immune escape driven by p53 inactivation.

As the most frequent genetic alteration in cancer, more than half of human cancers have p53 mutations that cause transcriptional inactivation. However, how p53 modulates the immune landscape to create a niche for immune escape remains elusive. We found that cancer stem cells (CSCs) established an interleukin-34 (IL-34)-orchestrated niche to promote tumorigenesis in p53-inactivated liver cancer. Mechanistically, we discovered that Il34 is a gene transcriptionally repressed by p53, and p53 loss resulted in IL-34 secretion by CSCs. IL-34 induced CD36-mediated elevations in fatty acid oxidative metabolism to drive M2-like polarization of foam-like tumor-associated macrophages (TAMs). These IL-34-orchestrated TAMs suppressed CD8+ T cell-mediated antitumor immunity to promote immune escape. Blockade of the IL-34-CD36 axis elicited antitumor immunity and synergized with anti-PD-1 immunotherapy, leading to a complete response. Our findings reveal the underlying mechanism of p53 modulation of the tumor immune microenvironment and provide a potential target for immunotherapy of cancer with p53 inactivation.

Ebi3 Binding to IFN-γ and IL-10 Limits Their Function.

EBV-induced gene 3 (Ebi3) is a ß subunit within the IL-12 cytokine family that canonically binds to α subunits p19, p28, or p35 to form the heterodimeric cytokines IL-39, IL-27, and IL-35, respectively. In the last decade, the binding partners for Ebi3 have continued to expand to include IL-6 and the other IL-12 family ß subunit p40, revealing the possibility that Ebi3 may be able to bind to other cytokines and have distinct functions. We first explored this possibility utilizing an in vivo mouse model of regulatory T cell-restricted deletions of the subunits composing the cytokine IL-35, p35, and Ebi3, and we observed a differential impact on CD8+ T cell inhibitory receptor expression despite comparable reduction in tumor growth. We then screened the ability of Ebi3 to bind to different cytokines with varying structural resemblance to the IL-12 family α subunits. These in vitro screens revealed extracellular binding of Ebi3 to both IFN-γ and IL-10. Ebi3 bound to IFN-γ and IL-10 abrogated signal transduction and downstream functions of both cytokines. Lastly, we validated that extracellular complex formation after mixing native proteins resulted in loss of function. These data suggest that secreted partnerless Ebi3 may bind to cytokines within the extracellular microenvironment and act as a cytokine sink, further expanding the potential immunological impact of Ebi3.

IL-27/Blimp-1 axis regulates the differentiation and function of Tim-3+ Tregs during early pregnancy.

Decidual regulatory T cells (Tregs) are essential for successful pregnancy outcome. A subset of Tregs, T cell immunoglobulin and mucin domain-containing protein 3-positive regulatory T cells (TregsTim-3+), plays a central role in the acceptance of the fetus during early stages of normal pregnancy. The molecular mechanism regulating the differentiation and function of TregsTim-3+ is unknown. Here, we investigated the role of the transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) on decidual TregTim-3+ differentiation. We demonstrated that Blimp-1 enhanced the coexpression of negative costimulatory molecules (Tim-3, T cell immunoreceptor with Ig and ITIM domains, and programmed cell death protein 1) on Tregs and improved their immunosuppressive functions, including increased IL-10 secretion, suppression of effector T cell proliferation, and promotion of macrophage polarization toward the M2 phenotype. Furthermore, we showed that IL-27 regulated the expression of Tim-3 and Blimp-1 through the STAT1 signaling pathway and that transfer of TregsBlimp-1+ into an abortion-prone mouse model effectively reduced embryo absorption rate. We postulated that abnormalities in the IL-27/Blimp-1 axis might be associated with recurrent pregnancy loss (RPL). These findings provided insights for developing more efficient immunotherapies for women with RPL.

[Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti-interleukins].

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gastrointestinal tract. The introduction of biologics, particularly anti-interleukin (IL) agents, has revolutionized IBD treatment. This review summarizes the role of ILs in IBD pathophysiology and describes the efficacy and positioning of anti-IL therapies. We discuss the functions of key ILs in IBD and their potential as therapeutic targets. The review then discusses anti-IL therapies, focusing primarily on ustekinumab (anti-IL-12/23), risankizumab (anti-IL-23), and mirikizumab (anti-IL-23). Clinical trial data demonstrate their efficacy in inducing and maintaining remission in Crohn's disease and ulcerative colitis. The safety profiles of these agents are generally favorable. However, long-term safety data for newer agents are still limited. The review also briefly discusses emerging therapies such as guselkumab and brazikumab. Network meta-analyses suggest that anti-IL therapies perform well compared to other biological agents. These agents may be considered first- or second-line therapies for many patients, especially those with comorbidities or safety concerns. Anti-IL therapies represent a significant advancement in IBD treatment, offering effective and relatively safe options for patients with moderate to severe disease.

LIM-domain-only 4 (LMO4) enhances CD8+ T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling.

High frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy trials. Herein, we analyzed a published CRISPR activation screening to identify transcriptional regulators that could be harnessed to augment stem-like behavior in CD8+ T cells. Using IFN-γ production as a proxy for CD8+ T cell terminal differentiation, LMO4 emerged among the top hits inhibiting the development of effectors cells. Consistently, we found that Lmo4 was downregulated upon CD8+ T cell activation but maintained under culture conditions facilitating the formation of stem-like T cells. By employing a synthetic biology approach to ectopically express LMO4 in antitumor CD8+ T cells, we enabled selective expansion and enhanced persistence of transduced cells, while limiting their terminal differentiation and senescence. LMO4 overexpression promoted transcriptional programs regulating stemness, increasing the numbers of stem-like CD8+ memory T cells and enhancing their polyfunctionality and recall capacity. When tested in syngeneic and xenograft tumor models, LMO4 overexpression boosted CD8+ T cell antitumor immunity, resulting in enhanced tumor regression. Rather than directly modulating gene transcription, LMO4 bound to JAK1 and potentiated STAT3 signaling in response to IL-21, inducing the expression of target genes (Tcf7, Socs3, Junb, and Zfp36) crucial for memory responses. CRISPR/Cas9-deletion of Stat3 nullified the enhanced memory signature conferred by LMO4, thereby abrogating the therapeutic benefit of LMO4 overexpression. These results establish LMO4 overexpression as an effective strategy to boost CD8+ T cell stemness, providing a new synthetic biology tool to bolster the efficacy of T cell-based immunotherapies.

Megalobrama amblycephala IL-22 attenuates Aeromonas hydrophila induced inflammation, apoptosis and tissue injury by regulating the ROS/NLRP3 inflammasome axis.

Mammalian interleukin-22 (IL-22) attenuates organismal injury by inhibiting reactive oxygen species (ROS) and impeding the NLRP3 inflammasome activation. However, the role of fish IL-22 in this process remains unclear. We characterized MaIL-22, an IL-22 homolog in blunt snout bream (Megalobrama amblycephala). Despite its low sequence identity, it shares conserved structures and close evolutionary relationships with other teleost IL-22s. Furthermore, Aeromonas hydrophila (A. hydrophila) infection leads to tissue injury in M. amblycephala immune organs and concomitantly altered Mail-22 mRNA expression, suggesting that MaIL-22 was involved in the antimicrobial immune response. To explore MaIL-22's biological functions, we produced recombinant MaIL-22 (rMaIL-22) protein and demonstrated it significantly enhanced the survival of M. amblycephala post-A. hydrophila infection. To unravel its protective mechanisms, we explored the ROS/NLRP3 inflammasome axis and its downstream signaling responses. The results showed that rMaIL-22 treatment significantly elevated antioxidant enzyme (T-SOD, CAT and GSH-PX) activities to inhibit MDA activity and scavenge ROS in visceral tissues. Meanwhile, rMaIL-22 impeded the activation of NLRP3 inflammasome by suppressing NLRP3 protein and mRNA expression. This indicated that rMaIL-22 contributed to inhibit A. hydrophila-induced activation of the ROS/NLRP3 inflammasome axis. Consistent with these findings, rMaIL-22 treatment attenuated the expression of proinflammatory cytokines (il-1ß, tnf-α and il-6) and proapoptotic genes (caspase-3 and caspase-8) while promoting antiapoptotic genes (bcl-2b and mcl-1a) expression, ultimately mitigating tissue injury in visceral tissues. In conclusion, our research underscores MaIL-22's key role in microbial immune regulation, offering insights for developing IL-22-targeted therapies and breeding programs.

Nucleophosmin 1 promotes mucosal immunity by supporting mitochondrial oxidative phosphorylation and ILC3 activity.

Nucleophosmin 1 (NPM1) is commonly mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia. Concurrent inflammatory bowel diseases (IBD) and MDS are common, indicating a close relationship between IBD and MDS. Here we examined the function of NPM1 in IBD and colitis-associated colorectal cancer (CAC). NPM1 expression was reduced in patients with IBD. Npm1+/- mice were more susceptible to acute colitis and experimentally induced CAC than littermate controls. Npm1 deficiency impaired the function of interleukin-22 (IL-22)-producing group three innate lymphoid cells (ILC3s). Mice lacking Npm1 in ILC3s exhibited decreased IL-22 production and accelerated development of colitis. NPM1 was important for mitochondrial biogenesis and metabolism by oxidative phosphorylation in ILC3s. Further experiments revealed that NPM1 cooperates with p65 to promote mitochondrial transcription factor A (TFAM) transcription in ILC3s. Overexpression of Npm1 in mice enhanced ILC3 function and reduced the severity of dextran sulfate sodium-induced colitis. Thus, our findings indicate that NPM1 in ILC3s protects against IBD by regulating mitochondrial metabolism through a p65-TFAM axis.

Interleukin-26 in channel catfish (Ictalurus punctatus): Molecular characterization and immune functional activity.

IL-26 is a crucial inflammatory cytokine that participates in defending host cells against infections. We initially cloned and identified the cDNA sequences of interleukin (IL)-26 in channel catfish (Ictalurus punctatus). The open reading frame (ORF) of IpIL-26 was 537 bp in length, encoding 178 amino acids (aa). Constitutive expression of IpIL-26 was observed in tested tissues, with the highest level found in the gill and spleen. To explore the function of IpIL-26 in channel catfish, different stimuli were used to act on both channel catfish and channel catfish kidney cells (CCK). The expression of IpIL-26 could be up-regulated by bacteria and viruses in multiple tissues. In vitro, recombinant IpIL-26 (rIpIL-26) could induce the expression levels of inflammatory cytokines such as TNF-α, IL-1ß, IL-6, IL-20, and IL-22 playing vital roles in defending the host against infections. Our results demonstrated that IpIL-26 might be an essential cytokine, significantly affecting the immune defense of channel catfish against pathogen infections.

A pathologically expanded, clonal lineage of IL-21-producing CD4+ T cells drives inflammatory neuropathy.

Inflammatory neuropathies, which include chronic inflammatory demyelinating polyneuropathy (CIDP) and Guillain Barré syndrome (GBS), result from autoimmune destruction of the PNS and are characterized by progressive weakness and sensory loss. CD4+ T cells play a key role in the autoimmune destruction of the PNS. Yet, key properties of pathogenic CD4+ T cells remain incompletely understood. Here, we used paired single-cell RNA-Seq (scRNA-Seq) and single-cell T cell receptor-sequencing (scTCR-Seq) of peripheral nerves from an inflammatory neuropathy mouse model to identify IL-21-expressing CD4+ T cells that were clonally expanded and multifunctional. These IL-21-expressing CD4+ T cells consisted of 2 transcriptionally distinct expanded cell populations, which expressed genes associated with T follicular helper (Tfh) and T peripheral helper (Tph) cell subsets. Remarkably, TCR clonotypes were shared between these 2 IL-21-expressing cell populations, suggesting a common lineage differentiation pathway. Finally, we demonstrated that IL-21 receptor-KO (IL-21R-KO) mice were protected from neuropathy development and had decreased immune infiltration into peripheral nerves. IL-21 signaling upregulated CXCR6, a chemokine receptor that promotes CD4+ T cell localization in peripheral nerves. Together, these findings point to IL-21 signaling, Tfh/Tph differentiation, and CXCR6-mediated cellular localization as potential therapeutic targets in inflammatory neuropathies.

Role of the type 3 cytokines IL-17 and IL-22 in modulating metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases that span simple steatosis, metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis and may progress to cirrhosis and cancer. The pathogenesis of MASLD is multifactorial and is driven by environmental, genetic, metabolic and immune factors. This review will focus on the role of the type 3 cytokines IL-17 and IL-22 in MASLD pathogenesis and progression. IL-17 and IL-22 are produced by similar adaptive and innate immune cells such as Th17 and innate lymphoid cells, respectively. IL-17-related signaling is upregulated during MASLD resulting in increased chemokines and proinflammatory cytokines in the liver microenvironment, enhanced recruitment of myeloid cells and T cells leading to exacerbation of inflammation and liver disease progression. IL-17 may also act directly by activating hepatic stellate cells resulting in increased fibrosis. In contrast, IL-22 is a pleiotropic cytokine with a dominantly protective signature in MASLD and is currently being tested as a therapeutic strategy. IL-22 also exhibits beneficial metabolic effects and abrogates MASH-related inflammation and fibrosis development via inducing the production of anti-oxidants and anti-apoptotic factors. A sex-dependent effect has been attributed to both cytokines, most importantly to IL-22 in MASLD or related conditions. Altogether, IL-17 and IL-22 are key effectors in MASLD pathogenesis and progression. We will review the role of these two cytokines and cells that produce them in the development of MASLD, their interaction with host factors driving MASLD including sexual dimorphism, and their potential therapeutic benefits.

[Progress of IL-21 and Tfh Mediated Immunotherapy in Non-small Cell Lung Cancer].

Non-small cell lung cancer (NSCLC) is a prevalent and aggressive global malignancy. Conventional surgical treatments, radiotherapy, chemotherapy, and targeted therapies often fall short in halting disease progression due to inherent limitations, resulting in suboptimal prognosis. Despite the advent of immunotherapy drugs offering new hope for NSCLC treatment, current efficacy remains insufficient to meet all patient needs. Therefore, actively exploring novel immunotherapeutic approaches to further reduce mortality rates in NSCLC patients has become a crucial focus of NSCLC research. This article aims to systematically review the anti-tumor effects of interleukin-21 and follicular helper T cells in NSCLC immunotherapy by summarizing and analyzing relevant literatures from both domestic and international sources, as well as exploring the potential for enhancing NSCLC treatment prospects through immune checkpoint regulation via immunotherapeutic means.
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Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD.

Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 NK cell potency while its overexpression increased NK cell long-term cytotoxicity and metabolic fitness. These results suggest that IL-21, through C/EBP transcription factors, drives epigenetic reprogramming of NK cells, enhancing their anti-tumor efficacy against GBM.

When playing the NK cell therapy card in glioblastoma, you can't beat interleukin-21.

Glioblastoma is the most common brain cancer, with a 5-year survival rate of less than 10%. This grim prognosis highlights the urgent need for novel therapeutic approaches. In this issue of Cancer Cell, Shanley et al.1 report an innovative engineering strategy to supercharge NK cell immunity against glioblastoma.

Fish IL-26 collaborates with IL-10R2 and IL-20R1 to enhance gut mucosal barrier during the antibacterial innate immunity.

IL-26 is a cytokine that is crucial for the maintenance and function of the gut mucosal barrier. IL-26 signaling pathway relies on a heterodimeric receptor complex, which is composed of two distinct subunits, IL-10R2 and IL-20R1. However, there are no reports on the antibacterial immunity of IL-26 and its receptors in fish. For this purpose, in this study we identified IL-26 and its receptors IL-10R2 and IL-20R1 in Carassius cuvieri × Carassius auratus red var. (named WR-IL-26, WR-IL10R2 and WR-IL20R1, respectively). Phylogenetic analysis confirmed the conservation of these genes, with shared structural motifs similar to those found in higher vertebrates. Upon exposure to Aeromonas hydrophila, a common fish pathogen, there was a significant upregulation of WR-IL-26, WR-IL10R2 and WR-IL20R1 in the gut, indicating a potential role in the immune response to infection. A co-immunoprecipitation assay revealed that WR-IL-26 formed complexes with WR-IL10R2 and WR-IL20R1. In vivo experiments demonstrated that administration of WR-IL-26 activated the JAK1-STAT3 signaling pathway and protected the gut mucosa barrier from A. hydrophila infection. Conversely, silencing WR-IL10R2 and WR-IL20R1 via RNA interference significantly attenuated the activation of WR-IL-26-mediated JAK1-STAT3 pathway. These results provided new insights into the role of IL-26 and its receptors in the gut mucosa barrier and could offer novel therapeutic strategies for managing bacterial infections in aquaculture.

The evolving landscape of IL-10, IL-22 and IL-26 in pleurisy especially in tuberculous pleurisy.

Pleurisy can be categorized as primary or secondary, arising from immunological, tumorous, or microbial conditions. It often results in lung structure damage and the development of various respiratory issues. Among the different types, tuberculous pleurisy has emerged as a prominent focus for both clinical and scientific investigations. The IL-10 family, known for its anti-inflammatory properties in the human immune system, is increasingly being studied for its involvement in the pathogenesis of pleurisy. This review aims to present a detailed overview of the intricate role of IL-10 family members (specifically IL-10, IL-22, and IL-26) in human and animal pleuritic diseases or relevant animal models. These insights could serve as valuable guidance and references for further studies on pleurisy and potential therapeutic strategies.