Cytokine Family Research Articles

Decreased Interleukin-1 Family Cytokine Production in Patients with Nontuberculous Mycobacterial Lung Disease.

Nontuberculous mycobacteria (NTM) cause pulmonary disease in individuals without obvious immunodeficiency. This study was initiated to gain insight into the immunological factors that predispose persons to NTM pulmonary disease (NTMPD). Blood was obtained from 15 pairs of NTMPD patients and their healthy household contacts. Peripheral blood mononuclear cells (PBMCs) were stimulated with the Mycobacterium avium complex (MAC). A total of 34 cytokines and chemokines were evaluated in plasma and PBMC culture supernatants using multiplex immunoassays, and gene expression in the PBMCs was determined using real-time PCR. PBMCs from NTMPD patients produced significantly less interleukin-1β (IL-1β), IL-18, IL-1α, and IL-10 than PBMCs from their healthy household contacts in response to MAC. Although plasma RANTES levels were high in NTMPD patients, they had no effect on IL-1β production by macrophages infected with MAC. Toll-like receptor 2 (TLR2) and TWIK2 (a two-pore domain K+ channel) were impaired in response to MAC in PBMCs of NTMPD patients. A TLR2 inhibitor decreased all four cytokines, whereas a two-pore domain K+ channel inhibitor decreased the production of IL-1β, IL-18, and IL-1α, but not IL-10, by MAC-stimulated PBMCs and monocytes. The ratio of monocytes was reduced in whole blood of NTMPD patients compared with that of healthy household contacts. A reduced monocyte ratio might contribute to the attenuated production of IL-1 family cytokines by PBMCs of NTMPD patients in response to MAC stimulations. Collectively, our findings suggest that the attenuated IL-1 response may increase susceptibility to NTM pulmonary infection through multiple factors, including impaired expression of the TLR2 and TWIK2 and reduced monocyte ratio. IMPORTANCE Upon MAC stimulation, the production of IL-1 family cytokines and IL-10 by PBMCs of NTMPD patients was attenuated compared with that of healthy household contacts. Upon MAC stimulation, the expression of TLR2 and TWIK2 (one of the two-pore domain K+ channels) was attenuated in PBMCs of NTMPD patients compared with that of healthy household contacts. The production of IL-1 family cytokines by MAC-stimulated PBMCs and MAC-infected monocytes of healthy donors was reduced by a TLR2 inhibitor and two-pore domain K+ channel inhibitor. The ratio of monocytes was reduced in whole blood of NTMPD patients compared with that of healthy household contacts. Collectively, our data suggest that defects in the expression of TLR2 and TWIK2 in human PBMCs or monocytes and reduced monocyte ratio are involved in the reduced production of IL-1 family cytokines, and it may increase susceptibility to NTM pulmonary infection.

New insights into Chlamydia pathogenesis: Role of leukemia inhibitory factor.

Chlamydia trachomatis (Ct) is the leading cause of bacterial sexually transmitted infections worldwide. Since the symptoms of Ct infection are often subtle or absent, most people are unaware of their infection until they are tested or develop severe complications such as infertility. It is believed that the primary culprit of Ct-associated tissue damage is unresolved chronic inflammation, resulting in aberrant production of cytokines, chemokines, and growth factors, as well as dysregulated tissue influx of innate and adaptive immune cells. A member of the IL-6 cytokine family, leukemia inhibitory factor (LIF), is one of the cytokines induced by Ct infection but its role in Ct pathogenesis is unclear. In this article, we review the biology of LIF and LIF receptor (LIFR)-mediated signaling pathways, summarize the physiological role of LIF in the reproductive system, and discuss the impact of LIF in chronic inflammatory conditions and its implication in Ct pathogenesis. Under normal circumstances, LIF is produced to maintain epithelial homeostasis and tissue repair, including the aftermath of Ct infection. However, LIF/LIFR-mediated signaling - particularly prolonged strong signaling - can gradually transform the microenvironment of the fallopian tube by altering the fate of epithelial cells and the cellular composition of epithelium. This harmful transformation of epithelium may be a key process that leads to an enhanced risk of infertility, ectopic pregnancy and cancer following Ct infection.

Dual Immune Regulatory Roles of Interleukin-33 in Pathological Conditions.

Interleukin-33 (IL-33), a member of the IL-1 cytokine family and a multifunctional cytokine, plays critical roles in maintaining host homeostasis and in pathological conditions, such as allergy, infectious diseases, and cancer, by acting on multiple types of immune cells and promoting type 1 and 2 immune responses. IL-33 is rapidly released by immune and non-immune cells upon stimulation by stress, acting as an “alarmin” by binding to its receptor, suppression of tumorigenicity 2 (ST2), to trigger downstream signaling pathways and activate inflammatory and immune responses. It has been recognized that IL-33 displays dual-functioning immune regulatory effects in many diseases and has both pro- and anti-tumorigenic effects, likely depending on its primary target cells, IL-33/sST2 expression levels, cellular context, and the cytokine microenvironment. Herein, we summarize our current understanding of the biological functions of IL-33 and its roles in the pathogenesis of various conditions, including inflammatory and autoimmune diseases, infections, cancers, and cases of organ transplantation. We emphasize the nature of context-dependent dual immune regulatory functions of IL-33 in many cells and diseases and review systemic studies to understand the distinct roles of IL-33 in different cells, which is essential to the development of more effective diagnoses and therapeutic approaches for IL-33-related diseases.

Calcium-Bound S100P Protein Is a Promiscuous Binding Partner of the Four-Helical Cytokines.

S100 proteins are multifunctional calcium-binding proteins of vertebrates that act intracellularly, extracellularly, or both, and are engaged in the progression of many socially significant diseases. Their extracellular action is typically mediated by the recognition of specific receptor proteins. Recent studies indicate the ability of some S100 proteins to affect cytokine signaling through direct interaction with cytokines. S100P was shown to be the S100 protein most actively involved in interactions with some four-helical cytokines. To assess the selectivity of the S100P protein binding to four-helical cytokines, we have probed the interaction of Ca2+-bound recombinant human S100P with a panel of 32 four-helical human cytokines covering all structural families of this fold, using surface plasmon resonance spectroscopy. A total of 22 cytokines from all families of four-helical cytokines are S100P binders with the equilibrium dissociation constants, Kd, ranging from 1 nM to 3 µM (below the Kd value for the S100P complex with the V domain of its conventional receptor, receptor for advanced glycation end products, RAGE). Molecular docking and mutagenesis studies revealed the presence in the S100P molecule of a cytokine-binding site, which overlaps with the RAGE-binding site. Since S100 binding to four-helical cytokines inhibits their signaling in some cases, the revealed ability of the S100P protein to interact with ca. 71% of the four-helical cytokines indicates that S100P may serve as a poorly selective inhibitor of their action.

The role of IL-1β during human immunodeficiency virus type1 infection.

Interleukin (IL)-1β is a key innate cytokine that is essential for immune activation and promoting the inflammatory process. However, abnormal elevation in IL-1β levels has been associated with unwanted clinical outcomes. IL-1β is the most extensively studied cytokine among the IL-1 family of cytokines and its role in pathology is well established. During the course of human immunodeficiency virus type 1 (HIV-1) infection, the level of this proinflammatory cytokine is increased in different anatomical compartments, particularly in lymphatic tissues, and this elevation is associated with disease progression. The aim of this review is to address the pathological roles play by IL-1β in the light of enhancing HIV-1 replication, driving immune cell depletion, and chronic immune activation. The role of IL-1β in HIV-1 transmission (sexually or vertically 'from mother-to-child') will also be discussed. Additionally, the impact of the available antiretroviral therapy regimens on the levels of IL-1β in HIV-1 treated patients is also discussed. Finally, we will provide a glance on how IL-1β could be targeted as a therapeutic strategy.

Critical roles of Parkin and PINK1 in antiviral immunity and protection from cell death in Enterovirus-induced viral myocarditis

Abstract Background Myocarditis is an inflammatory disease of the heart muscle often resulting in cardiac dysfunction and death. One of the most common causes is a cardiac infection with viruses, especially with enteroviruses of the Coxsackievirus B (CVB) family. CVB3-induced viral myocarditis is a well-established model to elucidate viral myocarditis in mice. It is assumed that mitochondrial damage control and mitochondria-associated innate immunity is essential for defence against viral infection of the heart muscle. And Parkinson's disease genes Parkin and PINK1 are well known for their critical function in mitochondrial homeostasis and damage control. We investigated the roles of Parkin and PINK1 in CVB3-induced viral myocarditis mouse model. Material and methods Male C57BL/6J WT, Parkin KO and PINK1 KO mice were used in an age of 8 to 12 weeks. The animals were injected intraperitoneally with 1x104 plaque forming units of CVB3 diluted in phosphate-buffered saline. Control and survived virus-infected mice were sacrificed for tissue sampling at day 7 to investigate imaging and molecular workup. Result After virus inoculation, the Parkin KO and PINK1 KO groups showed a significantly lower 28-day survival rate compared with the WT group (p<0.001 in Parkin KO; p<0.001 in PINK1 KO). Evans-Blue Dye (EBD) staining image of day 7 after virus-infection showed that the hearts of Parkin KO and PINK1 KO mice were more severely damaged than the hearts of WT mice (3.2-fold, p<0.01 in Parkin KO; 2.6-fold, p<0.05 in PINK1 KO). H&E staining showed that severe inflammatory reaction occurred in the hearts of WT mice, although the inflammatory reaction was much lower compared to WT in the hearts of Parkin KO and PINK1 KO mice (p<0.001 in Parkin KO; p<0.001 in PINK1 KO). In immunohistochemistry, EBD staining positive area colocalized well with CVB3 in Parkin KO and PINK1 KO mice hearts, although EBD staining positive area was rare and didn't colocalized well CVB3 in WT mice hearts. mRNA levels of cell markers (CD3, natural cytotoxicity receptors, F4/80), inflammatory cytokines (IL-1β, IL-6, TNF-α), type II interferon, macrophage-derived protective factors, and CXCL10 family cytokines were lower in virus-infected Parkin/PINK1 KO mice than WT mice. Western blots showed that phospho-p65 increased less than WT in the heart of Parkin KO (0.7-fold, p<0.05) and PINK1 KO mice (0.58-fold, p<0.05). Conclusion The Parkin KO and PINK1 KO mice showed a higher mortality rate and more severe cardiomyocyte damage than the WT mice in the viral myocarditis mouse model. Parkin and PINK1 is critical to the type II IFN pathway that inhibits virus replication. And Parkin and PINK1 play an important role in the recruitment of IFN-γ-producing lymphocytes through NF-κB pathway and CXCL10 family chemokines. Funding Acknowledgement Type of funding sources: None.

Serum interleukin-33 (IL-33) in children with active systemic lupus erythematosus: A cross-sectional study

Interleukin-33 (IL-33) is a member of the IL-1 cytokine family and is associated with the development of different autoimmune diseases as systemic lupus erythematosus (SLE). So, the purpose of this cross-sectional study was to measure the serum IL-33 in children with SLE (c-SLE) in relation to their SLE disease activity index. This study was conducted upon 50 c-SLE patients in comparison to 50 normal matched children as a control group. Disease activity was assessed according to SLE Disease Activity Index (SLEDAI-2K). Serum IL-33 was measured by an Enzyme-linked immunosorbent assay (ELISA). Serum IL-33 was significantly higher in c-SLE patients (median: 157.47, IQR:64.49-237.57ng/l) than controls (median: 10.9, IQR: 10.04-12.51ng/L) (P= 0.001) and negatively correlated with serum C3 and C4 levels. Serum IL-33 levels were significantly higher in high disease activity status (HDAS) patients (SLEDAI-2K ≥ 10) (298.47 ± 78.84ng/l) than lupus low disease activity status (LLDAS) patients (SLEDAI-2K < 10) (112.18 ± 16.23ng/l) (P= 0.001). The receiver operating characteristic (ROC) curve analysis revealed that the best cutoff of serum IL-33 level to predict the disease activity was ≥141.3 ng/l with a sensitivity of 93%, a specificity of 90% and accuracy 97%. We concluded that serum IL-33 was higher in c-SLE patients and positively related to the disease activity index so could be used as a disease activity marker.

Blockade of interleukin-33 activities by recombinant interleukin-33 Trap Fc protein would be a novel therapeutic strategy in allergic asthma

The majority of autoimmune and allergic diseases are associated with abnormal expression of interleukin (IL)-33, a member of the IL-1 family of cytokines, that function dually as a proinflammatory cytokine and a transcriptional factor. We created an IL-33 inhibitor called "IL-33 Trap Fc" constructed by fusion of an Fc fragment of human immunoglobulin G1 and two distinct extracellular part receptors involved in interacting with IL-33, IL-1 receptors accessory protein, and IL-33 receptor. IL-33 Trap Fc was expressed by two systems, mammalian HEK293 cells and Pichia pastoris yeast. We found that these recombinant proteins were expressed as a glycoprotein and perhaps in dimeric form. IL-33 Trap Fc from HEK293 and P. pastoris suppressed the activity of IL-33 in vitro culture conditions. The glycosylation of IL-33 Trap expressed by P. pastoris yeast was more intensive and heterogeneous than the counterpart protein expressed from HEK293 cells. That is maybe one reason leading to a substantial decrease in the activity of IL-33 Trap Fc from P. pastoris compared with that from HEK293 cells. We also demonstrated that IL-33 Trap Fc expressed from HEK293 cells had therapeutic effects in ovalbumin-induced asthma mouse model. These data collectively suggested that IL-33 Trap Fc potently blocks IL-33 in vitro and in vivo, which may be a novel therapeutic strategy for IL-33-mediated allergic diseases.

The IL-20RB receptor and the IL-20 signaling pathway in regulating host defense in oral mucosal candidiasis.

Pseudomembranous candidiasis (thrush), erythematous candidiasis, and fungal esophagitis are infections of the barrier mucosa of the upper gastrointestinal tract. The majority of these infections are caused by Candida albicans, an opportunistic fungal pathogen that frequently exists as a harmless commensal on mucosal surfaces lining the gastrointestinal tract. Oral infections are initiated in the superficial stratified squamous epithelium, in which keratinocytes are the most abundant host cells and are the initial points of contact with C. albicans present in saliva. Intrinsic features of oral keratinocytes are likely to play important roles in host defense and tissue homeostasis in oral candidiasis. One understudied pathway that may be important for modulating oral candidiasis is the IL-20 cytokine signaling pathway that employs keratinocyte IL-20RB receptors as ligands for IL-19, IL-20, and IL-24. We report that production of human oral keratinocyte il24 mRNA and protein are stimulated during co-culture with C. albicans. To test the role of the IL-20 family signaling pathway in oral candidiasis, Il20rb-/- mice (lacking the IL-20RB receptor) were compared to wild-type mice in a murine model of oropharyngeal candidiasis. Fungal burdens and percent loss in body weight were determined. Despite comparable fungal burdens, the Il20rb-/- mice exhibited less weight loss over the course of their infection compared to the B6 mice, suggestive of reduced overall disease consequences in the mutant mice. Interference with IL-20 family cytokine signaling may be useful for augmenting the ability of the host to defend itself against pathogens.

IL-10 cytokine family secretion is associated with the activity of mitophagy components in visceral adipose tissue in obese with and without type 2 diabetes mellitus

Autophagy is required to maintain cellular homeostasis and organ function by selectively ridding cells of potentially toxic proteins, lipids, and organelles. Impaired homeostasis of autophagic processes is associated with metabolic disorders such as obesity and type 2 diabetes mellitus. In obesity, a violation of autophagy in adipose tissue and its inflammation contributes to the formation of type 2 diabetes mellitus.&#x0D; The aim of the study was to analyze the expression of autophagy genes in the adipose tissue of the greater omentum and to search for their relationship with the levels of cytokines of the IL-10 family in blood plasma in obese patients, depending on the presence or absence of type 2 diabetes mellitus.&#x0D; Blood plasma and visceral adipose tissue samples were studied from 347 obese patients with and without type 2 diabetes. A biochemical analysis of the patients' blood was carried out. The level of cytokines was detected by flow fluorometry. Gene expression was determined by real-time PCR, and tissue-specific protein production was determined by immunoblotting. Statistical processing of the results was carried out using GraphPad Prism 9.0.0 software.&#x0D; Plasma levels of IL-10, IL-20, IL-22, IL-28A, and IL-29 are increased in obese patients without type 2 diabetes compared with patients with type 2 diabetes. In patients with type 2 diabetes mellitus, the expression of the SQSTM1_p62 and MAP1LC3B genes in the greater omentum increased compared to patients without it.&#x0D; High plasma levels of IL-22 and IL-26 are associated with the presence of type 2 diabetes mellitus. In patients without type 2 diabetes mellitus, an increase in the level of IL-28A in blood plasma is associated with a decrease in the expression of autophagy genes SQSTM1_p62 and MAP1LC3B in the adipose tissue of the greater omentum.

NLRP3 inflammasome: The rising star in cardiovascular diseases.

Cardiovascular diseases (CVDs) are the prevalent cause of mortality around the world. Activation of inflammasome contributes to the pathological progression of cardiovascular diseases, including atherosclerosis, abdominal aortic aneurysm, myocardial infarction, dilated cardiomyopathy, diabetic cardiomyopathy, heart failure, and calcific aortic valve disease. The nucleotide oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome plays a critical role in the innate immune response, requiring priming and activation signals to provoke the inflammation. Evidence shows that NLRP3 inflammasome not only boosts the cleavage and release of IL-1 family cytokines, but also leads to a distinct cell programmed death: pyroptosis. The significance of NLRP3 inflammasome in the CVDs-related inflammation has been extensively explored. In this review, we summarized current understandings of the function of NLRP3 inflammasome in CVDs and discussed possible therapeutic options targeting the NLRP3 inflammasome.

Bringing TRAP and NLRP3 into focus to Save EJ Populations

• BACKGROUND AND AIMS Whole city studies, especially in cooler climates in advanced economies, have found profoundly large chronic health effects for those living short distances from large regional transportation related air pollution and noise sources, such as busy roadways, relative to similar populations living a kilometer or more from these exposures. (Oslo, Stockholm, Vancouver, Toronto, Boston, Copenhagen). While primary pollutants like ultrafine particles and noise have steep gradients next to large TRAP sources, akin to these health effects, regional pollutants like PM2.5 and ozone have flat or inverse gradients. The spatiotemporal granularity of research required to show these TRAP relationships is more challenging than regional studies keyed on PM2.5 or Ozone (Six Cities vs CAFEH). • METHODS We conducted a literature review of NLRP3 inflammasome and particulates. • RESULTS and CONCLUSIONS Both ambient particulate matter and NLRP3 inflammasome biology, specifically, have been shown to accelerate many major diseases of inflammation – sterile and pathogenic. Inflammasomes generate Interleukin 1 family cytokines such as IL-1beta. Of the 21 human inflammasomes, only NLRP3 reacts strongly to exogenous and endogenous particles. NLRP3 drives the health effects of a broad array of exogenous particles, including manufactured adjuvants, medical imaging agents, mineral fibres and ambient TRAP. And of endogenous particles such as crystalized uric acid, amyloid tau tangles, cholesterol and high molecular weight fatty acids. Environmental justice (EJ) populations tend to concentrate in locations with high TRAP exposures. Without more focused research into environmental justice exposures, that integrates spatiotemporal knowledge of TRAP with NLRP3 immunology, we will be unable to protect these EJ populations. NLRP3 inflammasome biology may be the missing link between TRAP and EJ populations. • KEYWORDS Near source exposures, transportation related air pollution, NLRP3 inflammasome biology, high exposure environmental justice populations

Interleukin-17 Family Cytokines in Metabolic Disorders and Cancer.

Interleukin-17 (IL-17) family cytokines are potent drivers of inflammatory responses. Although IL-17 was originally identified as a cytokine that induces protective effects against bacterial and fungal infections, IL-17 can also promote chronic inflammation in a number of autoimmune diseases. Research in the last decade has also elucidated critical roles of IL-17 during cancer development and treatment. Intriguingly, IL-17 seems to play a role in the risk of cancers that are associated with metabolic disorders. In this review, we summarize our current knowledge on the biochemical basis of IL-17 signaling, IL-17′s involvement in cancers and metabolic disorders, and postulate how IL-17 family cytokines may serve as a bridge between these two types of diseases.

A STUB1 ubiquitin ligase/CHIC2 protein complex negatively regulates the IL-3, IL-5, and GM-CSF cytokine receptor common β chain (CSF2RB) protein stability

The IL-3, IL-5, and GM-CSF family of cytokines play an essential role in the growth, differentiation, and effector functions of multiple hematopoietic cell types. Receptors in this family are composed of cytokine-specific α chains and a common β chain (CSF2RB), responsible for the majority of downstream signaling. CSF2RB abundance and stability influence the magnitude of the cellular response to cytokine stimulation, but the exact mechanisms of regulation are not well understood. Here, we use genetic screens in multiple cellular contexts and cytokine conditions to identify STUB1, an E3 ubiquitin ligase, and CHIC2 as regulators of CSF2RB ubiquitination and protein stability. We demonstrate that Stub1 and Chic2 form a complex that binds Csf2rb and that genetic inactivation of either Stub1 or Chic2 leads to reduced ubiquitination of Csf2rb. The effects of Stub1 and Chic2 on Csf2rb were greatest at reduced cytokine concentrations, suggesting that Stub1/Chic2-mediated regulation of Csf2rb is a mechanism of reducing cell surface accumulation when cytokine levels are low. Our study uncovers a mechanism of CSF2RB regulation through ubiquitination and lysosomal degradation and describes a role for CHIC2 in the regulation of a cytokine receptor.

Molecular Characterization and Expression Analysis of Novel Interleukin-1 Family Member (nIL-1Fm) Gene in Nile Tilapia (Oreochromis niloticus)

In this study, a novel interleukin-1-family member (nIL-1Fm) was studied from the Nile tilapia (Oreochromis niloticus), a widely cultured fish species in brackish water and freshwater in Thailand and worldwide. The complete sequence of the Nile tilapia nIL-1Fm comprised 2474 bp, encoding 350 amino acids. The genome organization of nIL-1Fm had seven exons and six introns, which were conserved in teleost fish. During tissue distribution analysis, the nIL-1Fm was extremely increased in the head kidney, tailfin and trunk kidney, which had the highest levels, followed by the spleen. Additionally, nIL-1Fm was significantly up-regulated under PAMP stimulation, whereas the stimulation of LPS, PHA and poly I:C could significantly induce nIL-1Fm expression in vitro. Moreover, nIL-1Fm transcription was significantly induced when infected with Streptococcus agalactiae in the spleen, liver and intestine. Taking together, our results indicated that nIL-1Fm can expand our knowledge of the IL-1 cytokine family in fish immune response.

Efficacy of switches within the class of IL-17 inhibitors: An analysis of data from the Czech nationwide registry of psoriatic patients receiving biological/targeted therapy (BIOREP).

The IL-17 cytokine family encompasses six different homodimers and heterodimers referred to as IL-17A-F. Due to some differences in the mechanism of IL-17 inhibition, aninsufficient effect of one IL-17 inhibitor does not necessarily imply lack of efficacy of the other agent of the same class. Aim of study was analysis of the success rate of switches among IL-17 inhibitors (secukinumab, ixekizumab, and brodalumab) in patients treated in the Czech Republic. Data were obtained from the Czech nationwide registry of psoriatic patients receiving biological/targeted therapy (BIOREP). Our analysis involved data of a total of 90 patients with severe chronic plaque psoriasis and baseline PASI scores >10 both prior to first-line biological therapy initiation and after switch to another agent of the class of IL-17 inhibitors. The most effective switch was that from secukinumab to brodalumab, with PASI 90 reached by 64.7% and 73.3% of patients at weeks 12 and 24. Among patients switched from secukinumab to ixekizumab target PASI 90 responses were achieved (at weeks 12 and 24) by 41.2% and 55.2% of patients. Among patients switched from ixekizumab to brodalumab target PASI 90 responses were achieved, at the above time points, by 30.8% and 38.5% of patients. Our analysis showed a high success rate of switches from secukinumab to ixekizumab and brodalumab, followed by the ixekizumab-to-brodalumab switch. Importantly, the therapeutic response and success rates of individual switches are independent of the patient's body weight and presence of psoriatis arthritis.

Intrahepatic paracrine signaling by cardiotrophin-like cytokine factor 1 ameliorates diet-induced NASH in mice.

The mammalian liver harbors heterogeneous cell types that communicate via local paracrine signaling. Recent studies have delineated the transcriptomic landscape of the liver in NASH that provides insights into liver cell heterogeneity, intercellular crosstalk, and disease-associated reprogramming. However, the nature of intrahepatic signaling and its role in NASH progression remain obscure. Here, we performed transcriptomic analyses and identified cardiotrophin-like cytokine factor 1 (CLCF1), a member of the IL-6 family cytokines, as a cholangiocyte-derived paracrine factor that was elevated in the liver from diet-induced NASH mice and patients with NASH. Adenovirus-associated virus-mediated overexpression of CLCF1 in the liver ameliorated NASH pathologies in two diet-induced NASH models in mice, illustrating that CLCF1 induction may serve an adaptive and protective role during NASH pathogenesis. Unexpectedly, messenger RNA and protein levels of leukemia inhibitory factor receptor (LIFR), a subunit of the receptor complex for CLCF1, were markedly downregulated in NASH liver. Hepatocyte-specific inactivation of LIFR accelerated NASH progression in mice, supporting an important role of intrahepatic cytokine signaling in maintaining tissue homeostasis under metabolic stress conditions. Together, this study sheds light on the molecular nature of intrahepatic paracrine signaling during NASH pathogenesis and uncovers potential targets for therapeutic intervention.

Transcriptomic analysis reveals the genes involved in tetrodotoxin (TTX) accumulation, translocation, and detoxification in the pufferfish Takifugu rubripes.

Tetrodotoxin (TTX) is a potent marine neurotoxin that exists in a variety of aquatic and terrestrial organisms. Pufferfish in different habitats show great variation in their TTX contents. Exploring the genes involved in TTX metabolism could contribute to our understanding of the molecular mechanisms underlying TTX accumulation, translocation, and detoxification in pufferfish. In this study, transcriptomic analysis was used to identify the functional genes related to TTX metabolism in the blood, liver, and muscle of the toxic and non-toxic tiger puffer (Takifugu rubripes). A total of 6101 differentially expressed genes (DEGs) were obtained after transcriptomic analysis; of these, 2401 were identified in the blood, 2262 in the liver, and 1438 in the muscle. After enrichment analysis, fourteen genes encoding glutathione S-transferases (GSTs), glutathione peroxidase (GPx), thioredoxins (TXNs), superoxide dismutase (SOD), ATP-binding cassettes (ABCs), apolipoproteins (APOs), inhibitors of apoptosis protein (IAP), and solute carrier (SLC), which are mainly antioxidant enzymes, membrane transporters, or anti-apoptotic factors, were revealed in the blood. Thirty-six genes encoding SLCs, ABCs, long-chain-fatty-acid-CoA ligases (ACSLs), interleukin 6 cytokine family signal transducer (IL6ST), endoplasmic reticulum (ER), and heat shock protein family A (Hsp70) were involved in transmembrane transporter activity and innate immune response. Notably, a large number of slc genes were found to play critical and diverse roles in TTX accumulation and translocation in the liver of T. rubripes. Nine genes from the slc, hsp70, complement C5 (c5), acsl, er, and serpin peptidase inhibitor (serpin) gene families were found to participate in the regulation of protein processing and anti-apoptosis. These results reflect the diverse functions of genes closely related to TTX accumulation, translocation, and detoxification in T. rubripes.

Toxicity and bioactivity evaluation of interferon alpha-2b conjugated with solid lipid nanoparticles

Background: Interferon (IFN) are small proteins that belong to the cytokine family and may interfere with viral infections and some cancers. There are many studies focused on the PEGylated interferon’s bioactivity. In this study, we used solid lipid nanoparticles (SLNs) to produce new drug formulations, with the aim of reducing costs, increasing effectiveness, and also reducing side effects, and the biological effects of the formulation and comparing the obtained results with the interferon alpha-2b and PEGylated interferon alpha-2b.

Fasting-mimicking diet cycles reduce neuroinflammation to attenuate cognitive decline in Alzheimer's models.

The effects of fasting-mimicking diet (FMD) cycles in reducing many aging and disease risk factors indicate it could affect Alzheimer's disease (AD). Here, we show that FMD cycles reduce cognitive decline and AD pathology in E4FAD and 3xTg AD mouse models, with effects superior to those caused by protein restriction cycles. In 3xTg mice, long-term FMD cycles reduce hippocampal Aβ load and hyperphosphorylated tau, enhance genesis of neural stem cells, decrease microglia number, and reduce expression of neuroinflammatory genes, including superoxide-generating NADPH oxidase (Nox2). 3xTg mice lacking Nox2 or mice treated with the NADPH oxidase inhibitor apocynin also display improved cognition and reduced microglia activation compared with controls. Clinical data indicate that FMD cycles are feasible and generally safe in a small group of AD patients. These results indicate that FMD cycles delay cognitive decline in AD models in part by reducing neuroinflammation and/or superoxide production in the brain.