Serum interleukin-34 levels in dermatomyositis: a potential biomarker for anti-MDA5-antibody-associated interstitial lung disease.

OBJECTIVES: Interleukin (IL)-34 is a hematopoietic cytokine that promotes macrophage activation. Macrophage activation in interstitial lung disease (ILD) in patients with dermatomyositis (DM), especially in those with anti-melanoma differentiation-associated gene 5 (MDA5) antibody suggests the involvement of IL-34 in the disease. However, the association between IL-34 and DM is unknown. In this study, we aimed to determine serum IL-34 levels in DM patients and evaluate their association with DM-ILD. METHODS: We measured serum IL-34 levels in 56 DM patients and 14 age- and sex- matched healthy controls by enzyme-linked immunosorbent assay, and examined their correlation with clinical parameters. In addition, pre- and post-treatment serum IL-34 levels were examined using serum samples from 7 anti-MDA5 antibody-positive DM patients. RESULTS: Serum IL-34 levels were significantly elevated in DM patients, especially in those with anti-MDA5 antibody, compared with healthy controls. In anti-MDA5-antibody-positive DM patients, serum IL-34 levels positively correlated with serum levels of ferritin and anti-MDA5 antibody, which are known biomarkers for rapidly progressive (RP)-ILD. Following combined immunosuppressive therapy, serum IL-34 levels decreased along with ferritin and anti-MDA5 antibody. CONCLUSION: These data suggest that IL-34 may be involved in the development of RP-ILD in anti-MDA5 antibody-positive DM. Serum IL-34 levels can serve as a potential biomarker for RP-ILD in this clinical entity.

Two homologous genes encoding interleukin (IL)-34 in the common carp (Cyprinus carpio L.): roles in inflammatory modulation and anti-bacterial defense.

In mammals, interleukin 34 (IL-34) is a ligand for macrophage colony-stimulating factor receptor (M-CSFR), promoting inflammatory responses and inducing the synthesis and secretion of various cytokines. However, studies on its function in lower vertebrates is limited, and its evolutionary relationship with homologous molecules in mammals remains unclear. In this study, two IL-34-encoding genes were cloned and identified in common carp (Cyprinus carpio L.), designated as CcIL-34A and CcIL-34B, with an amino acid sequence similarity of 77.7%. Gene synteny analysis revealed that the IL-34 gene loci are relatively conserved, and both are located downstream of SF3B3. The expression patterns of CcIL-34s were analyzed using qRT-PCR, and this showed that they are expressed across all tested tissues, with higher levels in the liver, spleen, and head kidney and lower levels in the gills and intestines. Following infection with Aeromonas hydrophila, the mRNA expression levels of CcIL-34s in the gills, head kidney, intestines, and spleen were significantly upregulated. Immunofluorescence was also employed to assess changes in CcIL-34 protein expression, showing a significant increase in carp spleens 24 hours after A. hydrophila infection, suggesting that CcIL-34s contribute to host defense against this bacterium. To investigate the immunological function of IL-34 in vivo, pc-CcIL-34A and pc-CcIL-34B eukaryotic expression plasmids were constructed and injected intramuscularly into fish. Five days after injection, the expression levels of inflammation-related cytokines in the head kidney and spleen were significantly altered. Furthermore, 24 h post-A. hydrophila infection, the bacterial loads in the liver, spleen, and kidneys were significantly reduced. Ten days post-infection, the survival rates in the groups with CcIL-34A and CcIL-34B overexpression were 40% and 36.7%, respectively, compared to 16.7% in the control group. These findings suggest that CcIL-34s are involved in modulating inflammatory responses, enhancing the immune response, and improving survival rates in fish following bacterial infection, thus supporting the potential use of IL-34 molecules in aquaculture.

Tumor-derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by a lack of therapeutic targets. The paucity of effective treatment options motivated a number of studies to tackle this problem. Immunosuppressive cells infiltrated into the tumor microenvironment (TME) of TNBC are currently considered as candidates for new therapeutic targets. Myeloid-derived suppressor cells (MDSCs) have been reported to populate in the TME of TNBC, but their roles in the clinical and biological features of TNBC have not been clarified. This study identified that interleukin-34 (IL-34) released by TNBC cells is a crucial immunomodulator to regulate MDSCs accumulation in the TME. We provide evidence that IL-34 induces a differentiation of myeloid stem cells into monocytic MDSCs (M-MDSCs) that recruits regulatory T (Treg) cells, while suppressing a differentiation into polymorphonuclear MDSCs (PMN-MDSCs). As a result, the increase in M-MDSCs contributes to the creation of an immunosuppressive TME, and the decrease in PMN-MDSCs suppresses angiogenesis, leading to an acquisition of resistance to chemotherapy. Accordingly, blockade of M-MDSC differentiation with an estrogen receptor inhibitor or anti-IL-34 monoclonal antibody suppressed M-MDSCs accumulation causing retardation of tumor growth and restores chemosensitivity of the tumor by promoting PMN-MDSCs accumulation. This study demonstrates previously poorly understood mechanisms of MDSCs-mediated chemoresistance in the TME of TNBC, which is originated from the existence of IL-34, suggesting a new rationale for TNBC treatment.

Emerging roles of IL-34 in neurodegenerative and neurological infectious disease.

Neurological infections are often devastating in their clinical presentation. Although significant advances have made in neuroimaging techniques and molecular tools for diagnosis, as well as in anti-infective therapy, these diseases always difficult to diagnose and treat. Neuroparasitic infections and virus infections lead to neurological infections. In the nervous system, various cytokines and chemokines act as neuroinflammatory agents, neuromodulators, regulate neurodevelopment, and synaptic transmission. Among the most important cytokines, interleukins (ILs) are a large group of immunomodulatory proteins that elicit a wide variety of responses in cells and tissues. These ILs are involved in pro and anti-inflammatory effects, systemic inflammation, immune system modulation and play crucial roles in fighting cancer, infectious disease, and neurological disorders. Interleukin-34 (IL-34) identified by screening a comprehensive human protein library containing ∼3400 secreted and extracellular domain proteins in a human monocyte viability assay. Recent evidence has disclosed the crucial roles of IL-34 in the proliferation and differentiation of mononuclear phagocyte lineage cells, osteoclastogenesis, and inflammation. Additionally, IL-34 plays an important role in development, homeostasis, and disease. Dysregulation in IL-34 function can lead to various inflammatory and infectious diseases (e.g. Inflammatory bowel disease, liver fibrosis, Systemic Lupus erythematosus, rheumatoid arthritis), neurological disorders (e.g. Alzheimer disease) and neurological infectious disease (e.g. West Nile virus disease). In this review, we explore the biological role of IL-34 in addition to various impairments caused by dysregulation in IL-34 and discuss their potential links that may lead to important therapeutic and/or preventive strategies for these disorders.

IL-34 was high in serum of women with polycystic ovary syndrome and may function as potential diagnostic biomarker and therapeutic target.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorders in females of reproductive age, with a prevalence of 20%-33% in the general population. Interleukin (IL)-34 is a recently explored proinflammatory cytokine and is an important modulator in different disease types. However, the function of IL-34 in PCOS has yet to be investigated. OBJECTIVE: The purpose of this study was to determine the IL-34 serum level in women with PCOS and to compare it to that of a relatively healthy control group. Focusing on its relationship with IL-6, TNF-α, and IL-1ß and homeostatic model assessment for insulin resistance (HOMA-IR), triglyceride, and low-density lipoprotein cholesterol (LDL-C). MATERIALS AND METHODS: In this study, blood samples were obtained from 100 women with PCOS and 100 healthy control women for the purpose of estimating their serum levels of IL-34, IL-6, TNF-α, and IL-1ß using the enzyme-linked immunosorbent assay technique. RESULTS: Serum levels of IL-34, IL-6, TNF-α, and IL-1ß were all higher in PCOS women than in healthy controls, and the difference was highly statistically significant. Serum IL-34 concentration was positively correlated with IL-6, TNF-α, and IL-1ß concentration. Additionally, serum concentrations of IL-34 were positively correlated with HOMA-IR, triglyceride, and LDL-C. CONCLUSION: When compared to normal women, IL-34, IL-6, TNF-α, and IL-1ß levels were highly statistically significant in PCOS, and these high levels were associated with other cytokines (IL-6, TNF-α, and IL-1ß), HOMA-IR, triglyceride, and LDL-C.

Short-Term Immune Responses of Gilthead Seabream (Sparus aurata) Juveniles against Photobacterium damselae subsp. piscicida.

Photobacteriosis is a septicaemic bacterial disease affecting several marine species around the globe, resulting in significant economic losses. Although many studies have been performed related to the pathogen virulence and resistance factors, information regarding the host defence mechanisms activated once an infection takes place is still scarce. The present study was designed to understand innate immune responses of farmed juvenile gilthead seabream (Sparus aurata) after Photobacterium damselae subsp. piscicida (Phdp) infection. Therefore, two groups of seabream juveniles were intraperitoneally injected with 100 µL of PBS (placebo) or 100 µL of exponentially growing Phdp (1 × 106 CFU/mL; infected). The blood, plasma, liver, and head kidney of six fish from each treatment were sampled immediately before infection and 3, 6, 9, 24 and 48 h after infection for the broad screening of fish immune and oxidative stress responses. Infected animals presented marked anaemia, neutrophilia and monocytosis, conditions that are correlated with an increased expression of genes related to inflammation and phagocytic activity. Similar studies with different fish species and bacteria can be useful for the definition of health biomarkers that might help fish farmers to prevent the occurrence of such diseases.

Emerging roles of Interleukin-34 together with receptor activator of nuclear factor-kB ligand and osteoprotegerin levels in periodontal disease.

OBJECTIVE: The dependence between gingival crevicular fluid (GCF) of Interleukin-34 (IL-34) level and Receptor activator of nuclear factor -kB ligand/ osteoprotegerin (RANKL/OPG) ratio in the severity of periodontitis might reveal an unknown pathway of diseases with bone destruction. There is no study about the evaluation of IL-34 levels together with GCF RANKL and OPG levels in periodontitis patients before and after non-surgical periodontal treatment (NSPT). The objectives of this research were to investigate changes in the levels and relative ratios of IL-34, OPG, and RANKL in the GCF of patients with periodontitis before and after NSPT. MATERIALS AND METHODS: 20 healthy participants (CTRL), 20 patients with stage 3-grade B periodontitis and 20 with stage 3-grade C periodontitis were recruited. GCF and clinical periodontal recordings were investigated at the baseline and 6 weeks after NSPT. Enzyme-linked immunosorbent assay (ELISA) were used for quantifying of GCF IL-34, RANKL and OPG levels and their relative ratios were calculated. RESULTS: Greater values for GCF IL-34 and RANKL levels were found in the both of periodontitis groups than in CTRL group at baseline, whereas GCF OPG levels were statistically lower at baseline (P < 0.05). GCF IL-34 and RANKL levels decreased in the 6th week after NSPT in the both periodontitis groups, while the concentration OPG levels statistically increased (P < 0.05). Significantly positive correlations among the IL-34 with RANKL, sampled-site clinical attachment level (CAL), and gingival index (GI), whereas negative correlation with OPG were reported (P < 0.05). CONCLUSIONS: GCF IL-34 levels was high in patients with periodontitis and decreased after NSPT and its levels showed positive correlations with RANKL/OPG ratio levels CAL and GI. Determining of IL-34 levels together with RANKL/OPG ratio in GCF may therefore be valuable in detecting high risk individuals with periodontitis patients.

Interleukin-34 expression in ovarian cancer: a possible correlation with disease progression.

Ovarian cancer is the second-most lethal gynecological malignancy and the seventh-commonest cause of cancer-related death in women around the world. Most of the ovarian cancer patients are diagnosed at advanced stages and suffer from recurrence after primary cytoreductive surgery and standard first-line chemotherapy. Thus, the successful management of ovarian cancer patients requires the identification of factors that contribute to progression and relapse. Interleukin-34 (IL-34) is a novel cytokine that acts as a tissue-specific ligand of colony-stimulating factor-1 receptor (CSF-1R). In cancer, IL-34 exerts pro-tumorigenic functions that promote tumor growth, metastasis, angiogenesis, immune suppression and therapeutic resistance. In this study, we evaluate the impact of IL-34 on progression and survival of ovarian cancer patients. First, IL-34 was found to be expressed in several human ovarian cancer cell lines and cancer tissues from patients. The expression of IL-34 was enhanced by cytotoxic chemotherapy in ovarian cancer cell lines and cancer tissues from chemotherapy-treated ovarian cancer patients. Importantly, high IL-34 expression correlated with worse progression-free survival (PFS) and overall survival in different cohorts. The assessment of PFS based on a combination between IL34 expression and other related genes such as CSF1R and CD163 helped further to reach more statistical significance compared with IL34 alone. Furthermore, in the murine ovarian cancer cell HM-1 in vivo model, it was suggested that IL-34-derived tumor cells was correlated with tumor progression and survival by modulating the immune environment. Collectively, these findings indicate a possible correlation between IL-34 expression and disease progression in ovarian cancer patients and the mouse model.

Colony-stimulating factor-1 receptor blockade attenuates inflammation in inflamed gingival tissue explants.

BACKGROUND AND OBJECTIVE: Colony-stimulating factor-1 receptor (CSF-1R) regulates myeloid cell function and mediates osteoclastogenesis. CSF-1R blockade has been suggested as a potential therapeutic target to halt inflammation and bone resorption; however, the expression and function of CSF-1R in human gingiva is yet unknown. METHODS: Gingival tissue was collected from 22 non-periodontitis controls and 31 periodontitis (PD) patients. CSF-1R expression in gingival tissue was assessed with q-PCR, western blot, and immunohistochemistry (IHC). Cell surface expression of CSF-1R was analyzed by flow cytometry. The effects of CSF-1R inhibition on the production of inflammatory mediators by inflamed gingival tissue explants and peripheral blood mononuclear cells (PBMCs) were assessed with a bead-based multiplex array and ELISA. RESULTS: CSF-1R protein expression was increased in gingival tissue from PD patients compared with controls as assessed with western blot (1.5-fold increase) and IHC (4.5-fold increase). Similar proportions of HLA-DR+ CD64+ cells and comparable CSF-1R expression in this cell population were found in gingival tissue from PD patients and controls. In peripheral blood monocytes, CSF-1R was predominantly expressed by non-classical and intermediate monocytes. Targeting CSF-1R in gingival tissue explants attenuated the production of MMP-1, MMP-2, MMP-12, and MMP-13. The blocking in PBMCs attenuated the production of IL-8 and MMP-9. CONCLUSION: These results indicate that CSF-1R is elevated in PD, and its inhibition attenuates inflammatory mediators in the inflamed gingival tissue and circulating myeloid cells. Together these findings suggest that CSF-1R might be involved in regulating inflammatory processes in PD, and a potential therapeutic target to reduce the harmful inflammation.

Interleukin-34-CSF1R Signaling Axis Promotes Epithelial Cell Transformation and Breast Tumorigenesis.

IL-34 has been recently identified as a ligand for CSF1R that regulates various cellular processes including cell proliferation, survival, and differentiation. Although the binding of IL-34 to CSF1R modulates several cancer-driving signaling pathways, little is known about the role of IL-34/CSF1R signaling in breast cancer. Herein, we report that IL-34 induces epithelial cell transformation and breast tumorigenesis through activation of MEK/ERK and JNK/c-Jun pathways. IL-34 increased the phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun through CSF1R in mouse skin epidermal JB6 C141 cells and human breast cancer MCF7 cells. IL-34 enhanced c-Fos and c-Jun promoter activity, resulting in increased AP-1 transactivation activity in JB6 Cl41 and MCF7 cells. Moreover, PIN1 enhanced IL-34-induced phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun in JB6 Cl41 and MCF7 cells. Inhibition of PIN1 using juglone prevented the IL-34-induced transformation of JB6 C141 cells. Similarly, silencing of PIN1 reduced the IL-34-induced tumorigenicity of MCF7 cells. Consistent with these results, the synergistic model showed that treatment with juglone suppressed the IL-34-induced growth of tumors formed by 4T1 cells in BALB/c mice. Our study demonstrates the role of IL-34-induced MEK/ERK and JNK/c-Jun cascades in breast cancer and highlights the regulatory role of PIN1 in IL-34-induced breast tumorigenesis.

[Interleukin-34: a key molecule in the tumor microenvironment].

The tumor microenvironment (TME) acquires immune resistance during the process of tumor formation. Recently, cancer immunotherapy has been attracting attention as a treatment modality, following the three major standard cancer treatments (surgical therapy, radiation therapy, and chemotherapy), for its potential to overcome such an immunosuppressive TME. Particularly, blocking antibodies against immune checkpoint molecules, such as PD-1 and CTLA-4 have caused a paradigm shift in cancer treatment. However, several patients do not respond to existing cancer immunotherapy; therefore, the establishment of a novel therapeutic target is essential. Macrophages are the most abundant cells in various tumors and are biased toward immunosuppressive forms. Therefore, research is ongoing globally to determine whether macrophages could be therapeutic targets. Interleukin-34 (IL-34) has been reported as a factor that biases macrophages to immunosuppressive forms. It is expressed in various types of cancer cells and plays important roles in multiple aspects of the TME. In this review, we comprehensively introduce the roles of IL-34 in the TME.

IL-34 and coronary heart disease complicated with diabetes mellitus. / IL-34ä¸Žå† å¿ƒç— åˆå¹¶ç³–å°¿ç— .

Coronary heart disease and diabetes mellitus are closely related to chronic low-grade inflammation. Interleukin-34 (IL-34) is a new member of the interleukin family discovered in recent years. It is involved in the pathophysiological process of mononuclear phagocyte system mainly via binding to colony stimulating factor-1 receptor, and it is closely related to inflammatory and autoimmune diseases. IL-34 is highly expressed in patients with coronary heart disease or diabetes mellitus. IL-34 induces atherosclerosis and insulin resistance through multiple pro-inflammatory actions, ultimately leading to the occurrence and development of coronary heart disease, type 2 diabetes, and their comorbidities.

Interleukin 34 (IL-34) cell-surface localization regulated by the molecular chaperone 78-kDa glucose-regulated protein facilitates the differentiation of monocytic cells.

Interleukin 34 (IL-34) constitutes a cytokine that shares a common receptor, colony-stimulating factor-1 receptor (CSF-1R), with CSF-1. We recently identified a novel type of monocytic cell termed follicular dendritic cell-induced monocytic cells (FDMCs), whose differentiation depended on CSF-1R signaling through the IL-34 produced from a follicular dendritic cell line, FL-Y. Here, we report the functional mechanisms of the IL-34-mediated CSF-1R signaling underlying FDMC differentiation. CRIPSR/Cas9-mediated knockout of the Il34 gene confirmed that the ability of FL-Y cells to induce FDMCs completely depends on the IL-34 expressed by FL-Y cells. Transwell culture experiments revealed that FDMC differentiation requires a signal from a membrane-anchored form of IL-34 on the FL-Y cell surface, but not from a secreted form, in a direct interaction between FDMC precursor cells and FL-Y cells. Furthermore, flow cytometric analysis using an anti-IL-34 antibody indicated that IL-34 was also expressed on the FL-Y cell surface. Thus, we explored proteins interacting with IL-34 in FL-Y cells. Mass spectrometry analysis and pulldown assay identified that IL-34 was associated with the molecular chaperone 78-kDa glucose-regulated protein (GRP78) in the plasma membrane fraction of FL-Y cells. Consistent with this finding, GRP78-heterozygous FL-Y cells expressed a lower level of IL-34 protein on their cell surface and exhibited a reduced competency to induce FDMC differentiation compared with the original FL-Y cells. These results indicated a novel GRP78-dependent localization and specific function of IL-34 in FL-Y cells related to monocytic cell differentiation.

IL-34 regulates the inflammatory response and anti-bacterial immune defense of Japanese flounder Paralichthys olivaceus.

Interleukin (IL)-34 is a relatively recently discovered cytokine with pleiotropic effects on various cellular activities, including immune response. In fish, the knowledge on the function of IL-34 is limited. In the present work, we investigated the function of Japanese flounder Paralichthys olivaceus IL-34 (PoIL-34) in association with inflammation and immune defense. PoIL-34 possesses the conserved structure of IL-34 superfamily and shares 21.52% sequence identity with murine IL-34. PoIL-34 expression was detected in a wide range of tissues of flounder, in particular intestine, and was regulated to a significant extent by bacterial infection in a time-dependent fashion. In vitro studies showed that recombinant PoIL-34 (rPoIL-34) bound peripheral blood leukocytes (PBLs) and promoted ROS production, acid phosphatase activity, and cellular resistance against bacterial infection. At the molecular level, rPoIL-34 enhanced the expressions of inflammatory cytokines and specific JAK and STAT genes. Similar stimulatory effects of rPoIL-34 were observed in vivo. When PoIL-34 was overexpressed in flounder, the expressions of pro- and anti-inflammatory mediators were significantly affected in a tissue-dependent manner, which correlated with an augmented ability of the fish to eliminate invading pathogens from tissues. Together, these results indicated that PoIL-34 regulated inflammatory response probably via specific JAK/STAT pathways and had a significant influence on the immune defense of flounder against bacterial infection.

Effect of Interleukin-34 on Secretion of Angiogenesis Cytokines by Peripheral Blood Mononuclear Cells of Rheumatoid Arthritis.

BACKGROUND: Interleukin (IL)-34 is a new pro-inflammatory cytokine. Previous studies showed that IL-34 plays a key role in inflammation and osteoporosis in rheumatoid arthritis (RA). However, whether IL-34 participates in angiogenesis in RA remains unknown. Vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) play critical roles in the angiogenesis of RA. METHODS: 22 patients with RA, 18 patients with ankylosing spondylitis (AS), and 8 healthy subjects were enrolled in this study. Peripheral blood mononuclear cells (PBMCs) were isolated and purified from peripheral blood by density gradient centrifugation. PBMCs were stimulated using anti-CD3/CD28 antibody and different concentrations of recombinant human (rh) IL-34 (0, 10, 20, 50, 100 ng/mL). Cell-free supernatants were collected after 72 h incubation, and VEGF and HIF-1α levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: IL-34 promotes the secretion of VEGF and HIF-1α by PBMCs in RA patients in a dose-dependent manner. In contrast, IL-34 has no effect on VEGF and HIF-1α secretion by PBMCs in AS and healthy controls. CONCLUSION: IL-34 may indirectly contribute to angiogenesis by promoting the production of VEGF and HIF-1α and participate in the pathogenesis of RA.

IL-34 is a potential biomarker for the treatment of papillary thyroid cancer.

BACKGROUND: Interleukin (IL)-34 is a recently discovered pro-inflammatory cytokine and is a vital regulator in different tumor types. However, the function of IL-34 in thyroid carcinoma has yet to be investigated. In this study, we analyzed the expression of IL-34 in human papillary thyroid cancer (PTC) samples and determined its effects on the proliferation and apoptosis of PTC cells. METHODS: We examined the expression of IL-34 in serum and tissue samples of patients with PTC by Western blotting and ELISA assay and analyzed its association with clinicopathological features including tumor size, tumor node metastasis (TNM) stage, and lymph node metastasis (LNM). We selected TPC1 and K1 for knockdown or overexpressing of IL-34 via small interference RNA transfection. The proliferation of PTC cells was evaluated by CCK8 assay. We further investigated the role of IL-34 in apoptosis by flow cytometry and studied the protein levels of epithelial-mesenchymal transition (EMT) biomarkers, phosphorylated extracellular-regulated kinase (ERK), and total-ERK (t-ERK) by Western blotting. RESULTS: Our results show that IL-34 is significantly upregulated in serum and tissue samples from patients with PTC. IL-34 promotes the proliferation and suppresses apoptosis in PTC cells. In addition, IL-34 can promote the EMT and activate ERK signaling pathway in PTC cells. CONCLUSION: This study provides novel evidence that IL-34 serves as an oncogene in PTC. IL-34 promotes proliferation, EMT phenotype, and ERK signaling pathway and inhibits apoptosis in PTC cells. Therefore, IL-34 may be a potent therapeutic target for the treatment of PTC.

CSF-1 and IL-34 levels in peri-implant crevicular fluid and saliva from patients having peri-implant diseases.

OBJECTIVE: Colony-stimulating factor (CSF)-1 and interleukin (IL)-34 are growth factors that regulate myeloid cell functions and support osteoclastogenesis. CSF-1 and IL-34 levels in peri-implant diseases are yet unknown. This study evaluated CSF-1, IL-34, and IL-1ß levels in saliva and peri-implant crevicular fluid (PICF) from patients having mucositis or peri-implantitis, as well as their correlation to clinical parameters of disease. MATERIAL AND METHODS: Forty-three patients were included (mean age 61.1 ± 8.4; 62.8% female), 20 having mucositis and 23 having peri-implantitis. Patients were clinically examined and unstimulated whole saliva and PICF were collected. Levels of CSF-1, IL-34, and IL-1ß were determined by enzyme-linked immunosorbent assays. RESULTS: CSF-1 levels were higher in PICF from peri-implantitis compared with mucositis patients (p = 0.028), whereas IL-34 levels showed no significant difference between the groups (p = 0.060). No significant difference was found in PICF IL-1ß levels between the groups. Salivary levels of CSF-1 and IL-34 did not differ significantly between mucositis and peri-implantitis. No significant difference was observed in the salivary levels of IL-1ß between groups (p = 0.061). CSF-1 and IL-1ß correlated significantly in both saliva and PICF. CSF-1 levels in saliva correlated with its levels in PICF. PICF CSF-1 levels showed potential to discriminate between peri-implantitis and mucositis (AUC = 0.695, 95% CI 0.53-0.85; p = 0.029). CONCLUSION: Increased levels of CSF-1 in peri-implant crevicular fluid, but not in saliva, were found in peri-implantitis patients, which might aid to discriminate the early and late stages of peri-implant diseases. CLINICAL RELEVANCE: This result suggests an increased osteoclastogenic potential in peri-implantitis patients.

Interleukin-34, a Novel Paracrine/Autocrine Factor in Mouse Testis, and Its Possible Role in the Development of Spermatogonial Cells In Vitro.

Spermatogenesis is the process of spermatogonial stem cell (SSC) proliferation and differentiation to generate sperm. This process is regulated by cell-cell interactions between Sertoli cells and developing SSCs by autocrine/paracrine and endocrine factors. It is also affected by cells in the interstitial compartment, such as Leydig cells and peritubular cells. Here, we demonstrate, for the first time, the presence of interleukin-34 (IL-34) in Leydig, Sertoli, and peritubular cells and in the premeiotic, meiotic, and postmeiotic cells. Its receptor, colony-stimulating factor-1 (CSF-1), has already been demonstrated in Leydig, Sertoli, premeiotic, and meiotic cells. IL-34 was detected in testicular homogenates and Sertoli cell-conditioned media, and was affected by mouse age. We showed that the addition of IL-34 in vitro to isolated cells from the seminiferous tubules of 7-day-old mice, using the methylcellulose culture system (MCS), increased the percentages and expression of the premeiotic cells (VASA), the meiotic cells (BOULE), and the meiotic/postmeiotic cells (ACROSIN) after four weeks of culture, when examined by immunofluorescence staining (IF) and qPCR analysis. It is possible to suggest that IL-34 is a novel paracrine/autocrine factor involved in the development of spermatogenesis. This factor may be used in future therapeutic strategies for the treatment of male infertility.

The correlation between interleukin-34 and bone erosion under ultrasound in rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory arthropathy characterized by excessive synovial hyperplasia and progressive joint destruction. Pro-inflammatory cytokines play major roles in the regulation of synovial inflammation. The contribution of interleukin-34 (IL-34) in RA pathogenesis has been strongly suggested in clinical studies.Aim: To investigate the correlation between plasma IL-34 and disease parameters in RA patients including disease activity score (DAS28), receptor activator of NF-[Formula: see text]B ligand (RANKL) concentration, synovitis and bone erosions under ultrasound.Methods: 60 RA patients and 20 healthy controls were from Huashan Hospital, patient's medical history, physical examination, laboratory examination and ultrasound data were collected and recorded, respectively. Blood samples of all participants were collected and the levels of IL-34 and RANKL were tested. The levels of IL-34 and RANKL in RA patients were compared with those of healthy controls. Furthermore, the correlation between IL-34, RANKL and disease parameters in RA patients was analyzed.Results: Both plasma levels of IL-34 and RANKL in RA patients were significantly higher than the healthy controls (p < .05). IL-34 was significantly related to disease activity scores (r = 0.43, p = .001); RANKL (r = 0.46, p = .0003) and bone erosions by ultrasound (r = 0.38, p = .002).Conclusions: The plasma IL-34 concentration in RA was significantly higher than the healthy controls and was significantly correlated with RANKL, as well as disease activity score and bone erosions by ultrasound. The IL-34 may be a new biological marker for disease activity and predictor for bone erosions in RA. Targeting IL-34 holds promise in the management of RA and, potentially, other osteoclasts driven diseases (erosive osteoarthritis and psoriatic arthritis for example).

Differentiation-dependent antiviral capacities of amphibian (Xenopus laevis) macrophages.

Infections by ranaviruses such as Frog virus 3 (Fv3), are significantly contributing to worldwide amphibian population declines. Notably, amphibian macrophages (Mφs) are important to both the Fv3 infection strategies and the immune defense against this pathogen. However, the mechanisms underlying amphibian Mφ Fv3 susceptibility and resistance remain unknown. Mφ differentiation is mediated by signaling through the colony-stimulating factor-1 receptor (CSF-1R) which is now known to be bound not only by CSF-1, but also by the unrelated interleukin-34 (IL-34) cytokine. Pertinently, amphibian (Xenopus laevis) Mφs differentiated by CSF-1 and IL-34 are highly susceptible and resistant to Fv3, respectively. Accordingly, in the present work, we elucidate the facets of this Mφ Fv3 susceptibility and resistance. Because cellular resistance to viral replication is marked by expression of antiviral restriction factors, it was intuitive to find that IL-34-Mφs possess significantly greater mRNA levels of select restriction factor genes than CSF-1-Mφs. Xenopodinae amphibians have highly expanded repertoires of antiviral interferon (IFN) cytokine gene families, and our results indicated that in comparison with the X. laevis CSF-1-Mφs, the IL-34-Mφs express substantially greater transcripts of representative IFN genes, belonging to distinct gene family clades, as well as their cognate receptor genes. Finally, we demonstrate that IL-34-Mφ-conditioned supernatants confer IFN-mediated anti-Fv3 protection to the virally susceptible X. laevis kidney (A6) cell line. Together, this work underlines the differentiation pathways leading to Fv3-susceptible and -resistant amphibian Mφ populations and defines the molecular mechanisms responsible for these differences.