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Colony‐stimulating factor 2 (CSF2) plays a regulatory role in numerous cancers. However, there is needed to investigate the role of CSF2 in oral squamous cell carcinoma (OSCC) malignant phenotype and the specific mechanisms of CSF2 N‐6‐methyladenosine (m6A) modification. Therefore, we investigated the regulatory mechanism of m6A‐modified CSF2 by WT1‐associated protein (WTAP) in OSCC via qRT–PCR, western blot, WTAP and CSF2 overexpression in OSCC. In a panel of OSCCs, Kaplan–Meier plot analysis indicated that high expression of CSF2 was associated with poorer prognosis. Cell functional experiments revealed that enrichment of CSF2 promoted the proliferation and migration of OSCC cells by activating the JAK/STAT3 pathway, whereas the reduced expression of CSF2 resulted in the malignant decline of OSCC cells by blocking the JAK/STAT3 pathway. This study also confirmed that WTAP enhanced the m6A level of CSF2 and facilitated the expression of CSF2 and that CSF2 silencing blocked the invasive phenotype of OSCC cells and reversed the malignancy induced by WTAP overexpression. Overall, this study demonstrated that WTAP mediates the m6A modification of CSF2 and the JAK/STAT3 pathway, which plays an oncogenic role in the development of OSCC and can be a target for the treatment of patients with OSCC. [ABSTRACT FROM AUTHOR]

Acquired resistance is a major obstacle to the therapeutic efficacy of osimertinib in lung adenocarcinoma (LUAD), but the underlying mechanisms are still not fully understood. Cancer‐associated fibroblasts (CAFs) are the most abundant stromal cell type in LUAD tumor‐microenvironment (TME) and have emerged as a key player in chemoresistance. However, the function of CAFs in osimertinib resistance is still unclear. Here, we showed that CAFs derived from osimertinib‐resistant LUAD tissues (CAFOR) produced much more colony‐stimulating factor 2 (CSF2) than those isolated from osimertinib‐sensitive tissues. CAFOR‐derived CSF2 activated the Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) signaling pathway and upregulated lnc‐CSRNP3 in LUAD cells. Lnc‐CSRNP3 then promoted the expression of nearby gene CSRNP3 by recruiting chromodomain helicase DNA binding protein 9 (CHD9) and inhibited the phosphatase activity of the serine/threonine protein phosphatase 1 catalytic subunit α (PP1α), thereby induced osimertinib resistance by enhancing ribosome biogenesis. Collectively, our study reveals a critical role for CAFs in the development of osimertinib resistance and identifies the CSF2 pathway as an attractive target for monitoring osimertinib efficacy and overcoming osimertinib resistance in LUAD. [ABSTRACT FROM AUTHOR]

Abstract Acquired resistance is a major obstacle to the therapeutic efficacy of osimertinib in lung adenocarcinoma (LUAD), but the underlying mechanisms are still not fully understood. Cancer‐associated fibroblasts (CAFs) are the most abundant stromal cell type in LUAD tumor‐microenvironment (TME) and have emerged as a key player in chemoresistance. However, the function of CAFs in osimertinib resistance is still unclear. Here, we showed that CAFs derived from osimertinib‐resistant LUAD tissues (CAFOR) produced much more colony‐stimulating factor 2 (CSF2) than those isolated from osimertinib‐sensitive tissues. CAFOR‐derived CSF2 activated the Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) signaling pathway and upregulated lnc‐CSRNP3 in LUAD cells. Lnc‐CSRNP3 then promoted the expression of nearby gene CSRNP3 by recruiting chromodomain helicase DNA binding protein 9 (CHD9) and inhibited the phosphatase activity of the serine/threonine protein phosphatase 1 catalytic subunit α (PP1α), thereby induced osimertinib resistance by enhancing ribosome biogenesis. Collectively, our study reveals a critical role for CAFs in the development of osimertinib resistance and identifies the CSF2 pathway as an attractive target for monitoring osimertinib efficacy and overcoming osimertinib resistance in LUAD.

Desert dust exposure is associated with adverse respiratory health effects. Desert dust is a complex pollutant mixtures that includes respirable crystalline and amorphous particles, metals, and microbial constituents. Given the health effects of desert dust and its heterogeneity, as yet unidentified harmful biological pathways may be triggered. Therefore, we exposed human in vitro air–liquid interface co-cultures of alveolar epithelial A549 cells and THP-1 macrophages to Saharan dust (SD). For comparison, we used the known pulmonary toxicant DQ12 quartz dust. Via RNA sequencing, we identified that SD but not DQ12 increased the gene expression of granulocyte–macrophage colony-stimulating factor (GMCSF) and granulocyte colony-stimulating factor (GCSF). These findings were confirmed by quantitative reverse transcriptase PCR. SD dose-dependently upregulated GMCSF and GCSF expression with significant 7 and 9-fold changes, respectively, at the highest tested concentration of 31 µg/cm2. Furthermore, we observed that SD significantly enhanced the secretion of GM-CSF and G-CSF by 2-fold. Both cytokines have previously been associated with lung diseases such as asthma and fibrosis. Hence, we present two molecular messengers that may contribute to the adverse health effects of desert dust and might serve as drug targets for this globally relevant non-anthropogenic air pollutant.

IntroductionAutoantibodies against inflammatory cytokines may be used for the prevention of atherosclerosis. Preclinical studies consider colony-stimulating factor 2 (CSF2) as an essential cytokine with a causal relationship to atherosclerosis and cancer. We examined the serum anti-CSF2 antibody levels in patients with atherosclerosis or solid cancer.MethodsWe measured the serum anti-CSF2 antibody levels via amplified luminescent proximity homogeneous assay-linked immunosorbent assay based on the recognition of recombinant glutathione S-transferase-fused CSF2 protein or a CSF2-derived peptide as the antigen.ResultsThe serum anti-CSF2 antibody (s-CSF2-Ab) levels were significantly higher in patients with acute ischemic stroke (AIS), acute myocardial infarction (AMI), diabetes mellitus (DM), and chronic kidney disease (CKD) compared with healthy donors (HDs). In addition, the s-CSF2-Ab levels were associated with intima-media thickness and hypertension. The analyzes of samples obtained from a Japan Public Health Center-based prospective study suggested the utility of s-CSF2-Ab as a risk factor for AIS. Furthermore, the s-CSF2-Ab levels were higher in patients with esophageal, colorectal, gastric, and lung cancer than in HDs but not in those with mammary cancer. In addition, the s-CSF2-Ab levels were associated with unfavorable postoperative prognosis in colorectal cancer (CRC). In CRC, the s-CSF2-Ab levels were more closely associated with poor prognosis in patients with p53-Ab-negative CRC despite the lack of significant association of the anti-p53 antibody (p53-Ab) levels with the overall survival.ConclusionS-CSF2-Ab was useful for the diagnosis of atherosclerosis-related AIS, AMI, DM, and CKD and could discriminate poor prognosis, especially in p53-Ab-negative CRC.

The developmental program of the embryo displays a plasticity that can result in long-acting effects that extend into postnatal life. In mammals, adult phenotype can be altered by changes in the maternal environment during the preimplantation period. One characteristic of developmental programming during this time is that the change in adult phenotype is often different for female offspring than for male offspring. In this paper, we propose the hypothesis that sexual dimorphism in preimplantation programming is mediated, at least in part, by sex-specific responses of embryos to maternal regulatory molecules whose secretion is dependent on the maternal environment. The strongest evidence for this idea comes from the study of colony-stimulating factor 2 (CSF2). Expression of CSF2 from the oviduct and endometrium is modified by environmental factors of the mother, in particular seminal plasma and obesity. Additionally, CSF2 alters several properties of the preimplantation embryo and has been shown to alleviate negative consequences of culture of mouse embryos on postnatal phenotype in a sex-dependent manner. In cattle, exposure of preimplantation bovine embryos to CSF2 causes sex-specific changes in gene expression, interferon-τ secretion and DNA methylation later in pregnancy (day 15 of gestation). It is likely that several embryokines can alter postnatal phenotype through actions directed towards the preimplantation embryo. Identification of these molecules and elucidation of the mechanisms by which sexually-disparate programming is established will lead to new insights into the control and manipulation of embryonic development.

[Display omitted] • RNA sequencing was applied to an alveolar air–liquid interface co-culture model. • Different inflammatory mediators were activated by Saharan dust and quartz dust. • Saharan dust induced the lung disease-related cytokines GM-CSF and G-CSF. Desert dust exposure is associated with adverse respiratory health effects. Desert dust is a complex pollutant mixtures that includes respirable crystalline and amorphous particles, metals, and microbial constituents. Given the health effects of desert dust and its heterogeneity, as yet unidentified harmful biological pathways may be triggered. Therefore, we exposed human in vitro air–liquid interface co-cultures of alveolar epithelial A549 cells and THP-1 macrophages to Saharan dust (SD). For comparison, we used the known pulmonary toxicant DQ12 quartz dust. Via RNA sequencing, we identified that SD but not DQ12 increased the gene expression of granulocyte–macrophage colony-stimulating factor (GMCSF) and granulocyte colony-stimulating factor (GCSF). These findings were confirmed by quantitative reverse transcriptase PCR. SD dose-dependently upregulated GMCSF and GCSF expression with significant 7 and 9-fold changes, respectively, at the highest tested concentration of 31 µg/cm2. Furthermore, we observed that SD significantly enhanced the secretion of GM-CSF and G-CSF by 2-fold. Both cytokines have previously been associated with lung diseases such as asthma and fibrosis. Hence, we present two molecular messengers that may contribute to the adverse health effects of desert dust and might serve as drug targets for this globally relevant non-anthropogenic air pollutant. [ABSTRACT FROM AUTHOR]

Myeloid‐derived suppressor cells (MDSCs) are known to contribute to tumour immune evasion, and studies have verified that MDSCs can induce cancer stem cells (CSCs) and promote tumour immune evasion in breast cancers, cervical cancers and glioblastoma. However, the potential function of MDSCs in regulating CSCs in epithelial ovarian cancer (EOC) progression is unknown. Our results indicated that compared to nonmalignant ovarian patients, EOC patients showed a significantly increased proportion of MDSCs in the peripheral blood. In addition, MDSCs dramatically promoted tumour sphere formation, cell colony formation and CSC accumulation, and MDSCs enhanced the expression of the stemness biomarkers NANOG and c‐MYC in EOC cells during coculture. Moreover, the mechanisms by which MDSCs enhance EOC stemness were further explored, and 586 differentially expressed genes were found in EOC cells cocultured with or without MDSCs; during coculture, the expression level of colony‐stimulating factor 2 (CSF2) was significantly increased in EOC cells cocultured with MDSCs. Furthermore, the depletion of CSF2 in EOC cells was successfully performed, the promotive effects of MDSCs on EOC cell stemness could be markedly reversed by downregulating CSF2 expression, p‐STAT3 signalling pathway molecules were also altered, and the p‐STAT3 inhibitor could markedly reverse the promotive effects of MDSCs on EOC cell stemness. In addition, the CSF2 expression level was correlated with EOC clinical staging. Therefore, MDSCs enhance the stemness of EOC cells by inducing the CSF2/p‐STAT3 signalling pathway. Targeting MDSCs or CSF2 may be a reasonable strategy for enhancing the efficacy of conventional treatments. Database: Gene expression data files are available in the GEO databases under the accession number(s) GSE145374. [ABSTRACT FROM AUTHOR]

While dysbiosis in the gut is implicated in the impaired induction of oral tolerance generated in mesenteric lymph nodes (MesLNs), how dysbiosis affects this process remains unclear. Here, we describe that antibiotic-driven gut dysbiosis causes the dysfunction of CD11c+CD103+ conventional dendritic cells (cDCs) in MesLNs, preventing the establishment of oral tolerance. Deficiency of CD11c+CD103+ cDCs abrogates the generation of regulatory T cells in MesLNs to establish oral tolerance. Antibiotic treatment triggers the intestinal dysbiosis linked to the impaired generation of colony-stimulating factor 2 (Csf2)-producing group 3 innate lymphoid cells (ILC3s) for regulating the tolerogenesis of CD11c+CD103+ cDCs and the reduced expression of tumor necrosis factor (TNF)-like ligand 1A (TL1A) on CD11c+CD103+ cDCs for generating Csf2-producing ILC3s. Thus, antibiotic-driven intestinal dysbiosis leads to the breakdown of crosstalk between CD11c+CD103+ cDCs and ILC3s for maintaining the tolerogenesis of CD11c+CD103+ cDCs in MesLNs, responsible for the failed establishment of oral tolerance. [Display omitted] • CD103+ cDCs are prerequisite for establishing oral tolerance • Intestinal dysbiosis leads to the abortive establishment of oral tolerance • Intestinal dysbiosis results in loss of the tolerogenesis of CD103+ cDCs • Intestinal dysbiosis hampers crosstalk between CD103+ cDCs and ILC3s Intestinal dysbiosis hampers the establishment of oral tolerance. Fukaya et al. provide insight into the underlying mechanisms by showing that intestinal dysbiosis impairs the crosstalk between CD103+ cDCs and ILC3s, which impairs the tolerogenesis of CD103+ cDCs, abolishing the establishment of oral tolerance. [ABSTRACT FROM AUTHOR]

Introduction: Autoantibodies against inflammatory cytokines may be used for the prevention of atherosclerosis. Preclinical studies consider colony-stimulating factor 2 (CSF2) as an essential cytokine with a causal relationship to atherosclerosis and cancer. We examined the serum anti-CSF2 antibody levels in patients with atherosclerosis or solid cancer., Methods: We measured the serum anti-CSF2 antibody levels via amplified luminescent proximity homogeneous assay-linked immunosorbent assay based on the recognition of recombinant glutathione S-transferase-fused CSF2 protein or a CSF2-derived peptide as the antigen., Results: The serum anti-CSF2 antibody (s-CSF2-Ab) levels were significantly higher in patients with acute ischemic stroke (AIS), acute myocardial infarction (AMI), diabetes mellitus (DM), and chronic kidney disease (CKD) compared with healthy donors (HDs). In addition, the s-CSF2-Ab levels were associated with intima-media thickness and hypertension. The analyzes of samples obtained from a Japan Public Health Center-based prospective study suggested the utility of s-CSF2-Ab as a risk factor for AIS. Furthermore, the s-CSF2-Ab levels were higher in patients with esophageal, colorectal, gastric, and lung cancer than in HDs but not in those with mammary cancer. In addition, the s-CSF2-Ab levels were associated with unfavorable postoperative prognosis in colorectal cancer (CRC). In CRC, the s-CSF2-Ab levels were more closely associated with poor prognosis in patients with p53-Ab-negative CRC despite the lack of significant association of the anti-p53 antibody (p53-Ab) levels with the overall survival., Conclusion: S-CSF2-Ab was useful for the diagnosis of atherosclerosis-related AIS, AMI, DM, and CKD and could discriminate poor prognosis, especially in p53-Ab-negative CRC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Yoshida, Kubota, Zhang, Matsutani, Ito, Yajima, Yoshida, Mine, Machida, Hayashi, Takemoto, Yokote, Ohno, Nishi, Kitamura, Kamitsukasa, Takizawa, Sata, Yamagishi, Iso, Sawada, Tsugane, Iwase, Shimada, Iwadate and Hiwasa.)

Loureiro B, Oliveira LJ, Favoreto MG, Hansen PJ. Colony-stimulating factor 2 inhibits induction of apoptosis in the bovine preimplantation embryo. Am J Reprod Immunol 2011; 65: 578-588 Addition of colony-stimulating factor 2 (CSF2) to culture medium increases post-transfer survival of bovine embryos. Here we provide evidence that one mechanism by which CSF2 affects the embryo is through inhibition of apoptosis. In the first experiment, genes and pathways whose expression were regulated by CSF2 were identified by microarray analysis. Embryos were treated with 10 ng/ml CSF2 or vehicle at Day 5 after insemination; morulae were selected for microarray analysis at Day 6. In a second experiment, antiapoptotic effects of CSF2 were determined. Embryos were treated with CSF2 or vehicle at Day 5. On Day 6 (24 h after treatment), morulae were cultured for 15 h at either 42°C (a temperature that induces apoptosis) or 38.5°C (cow body temperature). In the first experiment, a total of 214 genes were differentially regulated and 160 of these could be annotated (67 upregulated genes and 93 downregulated genes). Differentially expressed genes could be placed in 13 biological process ontologies in four functional groups (development and differentiation process, cell communication, apoptosis and cell adhesion). Antiapoptotic effects of CSF2 were confirmed in the second experiment because the magnitude of the increase in TUNEL positive cells caused by heat shock was reduced by CSF2. CSF2 blocks apoptosis in bovine embryos through actions associated with regulation of genes controlling apoptosis. [ABSTRACT FROM AUTHOR]

Oral Diseases (2010) 16, 343–350 Objective: Toll-like receptors (TLRs) are the essential components in the innate and adaptive immune systems. Colony stimulating factor 2 (CSF2) is a cytokine that may prevent endotoxin tolerance, and LY64 has the ability to interfere with the recognition of bacteria via TLR4. The aim of this study was to explore the in vivo expressions of TLR2, TLR4, CSF2 and LY64 in Chinese chronic periodontitis patients. Methods: Gingival biopsies were collected from 24 chronic periodontitis patients and 19 healthy controls. The gene expression profiles of TLR2, TLR4, CSF2 and LY64 were investigated by real-time polymerase chain reaction, and the protein expressions of TLR2 and TLR4 were detected by immunohistochemistry. In addition, the levels of CSF2 in gingival crevicular fluid (GCF) were determined by ELISA. Results: The higher mRNA expressions of TLR2, TLR4 and CSF2, and the lower mRNA expression of LY64 were detected in chronic periodontitis patients. And the increased protein expressions of TLR2 and TLR4 were confirmed by immunohistochemistry. In addition, the increase of total amount of CSF2 in GCF was observed in chronic periodontitis patients. Conclusions: Our results suggest that TLR2 and TLR4 may play a role in periodontal pathogenesis. In addition, CSF2 and LY64 may contribute to the regulation of inflammatory response and maintaining periodontal homeostasis. [ABSTRACT FROM AUTHOR]

Colony-stimulating factor 2 (CSF2) is an embryokine that improves competence of the embryo to establish pregnancy and which may participate in developmental programming. We tested whether culture of bovine embryos with CSF2 alters fetal development and alleviates abnormalities associated with in vitro production (IVP) of embryos. Pregnancies were established by artificial insemination (AI), transfer of an IVP embryo (IVP), or transfer of an IVP embryo treated with 10 ng/ml CSF2 from day 5 to 7 of development (CSF2). Pregnancies were produced using X-sorted semen. Female singleton conceptuses were collected on day 86 of gestation. There were few morphological differences between groups, although IVP and CSF2 fetuses were heavier than AI fetuses. Bicarbonate concentration in allantoic fluid was lower for IVP than for AI or CSF2. Expression of 92 genes in liver, placenta, and muscle was determined. The general pattern for liver and placenta was for IVP to alter expression and for CSF2 to sometimes reverse this effect. For muscle, CSF2 affected gene expression but did not generally reverse effects of IVP. Levels of methylation for each of the three tissues at 12 loci in the promoter of insulin-like growth factor 2 (IGF2) and five in the promoter of growth factor receptor bound protein 10 were unaffected by treatment except for CSF2 effects on two CpG for IGF2 in placenta and muscle. In conclusion, CSF2 can act as a developmental programming agent but alone is not able to abolish the adverse effects of IVP on fetal characteristics., (© The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please journals.permissions@oup.com.)

Physiology of the adult can be modified by alterations in prenatal development driven by the maternal environment. Developmental programming, which can be established before the embryo implants in the uterus, can affect females differently than males. The mechanism by which sex-specific developmental programming is established is not known. Here we present evidence that maternal regulatory signals change female embryos differently than male embryos. In particular, actions of the maternally derived cytokine CSF2 from Day 5 to Day 7 of development affected characteristics of the embryo at Day 15 differently for females than males. CSF2 decreased length and IFNT secretion of female embryos but increased length and IFNT secretion of male embryos. Analysis of a limited number of samples indicated that changes in the transcriptome and methylome caused by CSF2 also differed between female and males. Thus, sex-specific programming by the maternal environment could occur when changes in secretion of maternally derived regulatory molecules alter development of female embryos differently than male embryos., (© 2014 by the Society for the Study of Reproduction, Inc.)