key: cord-0004120-qt8ocxtr authors: Cai, Xulong; Zhou, Chenrong; Zhou, Li; Xu, Qiaolan title: A bibliometric analysis of IL-35 research from 2009 to 2018 date: 2019-10-30 journal: PeerJ DOI: 10.7717/peerj.7992 sha: 80ae0645a59c66f34ce7fe53fba4a00404b1c740 doc_id: 4120 cord_uid: qt8ocxtr BACKGROUND: Interleukin-35 (IL-35) is a recently discovered cytokine that plays a role in immune suppression and has therefore been the subject of a great deal of research. A bibliometric analysis of the global research concerning IL-35, however, is rare. OBJECTIVES: The aim of this research was to assess the international scientific output of IL-35 research and explore its hotspots and frontiers from 2009 to 2018 by bibliometric analysis. METHODS: Publications about IL-35 research from 2009 to 2018 were retrieved from the Web of Science Core Collection (WoSCC). Citespace V was used to analyze years, journals, countries, research institutions, areas of exploration, research hotspots, and trends of publication. RESULTS: We retrieved a total of 416 publications and observed a trend of publications increasing over the past decade. Original articles (351) were the most frequently occurring document type. The largest number of publications belonging to one country and one institution, respectively, was China (202) and Tianjin Medical University (17). Trending keywords may indicate frontier topics, including “infectious tolerance,” “autoimmune,” and “central nervous system.” CONCLUSION: This study provides valuable information on the study of IL-35 so that researchers may identify new research fields. In 1997, a study reported that the Epstein-Barr Virus-Induced Gene 3 Protein (EBI3) associated noncovalently with the p35 subunit of interleukin −12 to form a heterodimeric hematopoietin in vivo (Devergne, Birkenbach & Kieff, 1997) . The EBI3-p35 heterodimer has been named IL-35 by the International Union of Immunological Societies (IUIS) Subcommittee. The cytokine IL-35 has been identified as a member of the IL-12 family. Other IL-12 family cytokines include IL-12, IL-23, and IL-27. IL-12 and IL-23 are both considered pro-inflammatory cytokines (Devergne, Birkenbach & Kieff, 1997) . As an effective T cell immunomodulator, IL-27 has anti-inflammatory and pro-inflammatory properties (Thompson & Orr, 2018) . Interleukin-35, however, was identified as an inhibitory cytokine in 2007 (Collison et al., 2007) , indicating that IL-35 is quite different from other members of IL-12 family cytokines. (Collison et al., 2007; Shen et al., 2014) . It has been shown that IL-35 inhibits the proliferation of T cells and induces the conversion of naïve T cells into iTr35 cells (Collison et al., 2007; Collison et al., 2010) . IL-35 activated STAT1/STAT3 by means of an IL-35 receptor, and induced human B cells to transform into regulatory B-cells (Wang et al., 2014) . After proinflammatory cytokines (tumor necrosis factor-a, interferon-γ, and IL-1β) provoke inflammation, IL-35 can be upregulated in human non-T cells, such as intestinal microvascular endothelial cells, primary aortic smooth muscle cells, and intestinal epithelial cell (Li et al., 2012) . Studies have suggested that IL-35 is involved in autoimmune diseases, tumor progression, type II immune response, and infectious tolerance (Wang et al., 2014; Olson, Sullivan & Burlingham, 2013; Su et al., 2018; Shamji et al., 2019; Chatrabnous et al., 2019) . Interest in research on IL-35 has increased dramatically in recent years, and as a result, many journals have published articles on IL-35. The rapid growth of IL-35 literature renders identifying new developments and emerging trends in IL-35 research difficult. Few attempts, however, have been made to systematically analyze the knowledge, intellectual turning points, and key points in this field. CiteSpace is a tool for visualizing and analyzing trends and patterns in scientific papers (Chen, 2004) . CiteSpace provides a variety of functions to help understand network and historical patterns, including identifying rapidly growing subject areas, finding citation hotspots, decomposing networks into clusters, and automatically labeling clusters with citation terms (Chen, 2006) . Here, we used bibliometric analysis to qualitatively and quantitatively evaluate IL-35 studies from 2009 to 2018. It is expected, therefore, that CiteSpace could be used to identify the emerging trends and hotspots of IL-35 research. All of the data obtained from the Web of Science Core Collection (WoSCC) of Thomson Reuters on February 27, 2019 was used in this study. The data retrieval strategy was: topic: (Interleukin-35) OR topic: (IL-35), index = SCI-EXPANDED, time span = 2009-2018 (retrieved date February 27, 2019). The following search string was used: document type: (Article OR Review). Web of Science database was used to analyze the characteristics of the literature, including the countries or regions in which it was conducted, the organization that researched IL-35, the journals it was published, as well as the research areas. The downloaded document records were exported to CiteSpace V for the further analysis. We collected 416 papers on IL-35 the WoSCC. Of these, 351 (84.38%) were original articles. The number of published research papers increased during the years from 2009 (n = 6) to 2018 (n = 89). The number of citations of these papers also increased dramatically from 2009 (n = 11) to 2018 (n = 2,171) ( Fig. 1) , reaching a total of 8166. There were 350 (84.13%) papers that had been cited at least once. Table 1 shows the 10 most frequently cited publications. A total of 191 different journals published these articles. The maximum number of papers published in Cytokine was 19, followed by PLoS One (n = 16), the Journal of Immunology (n = 14), and Frontiers in Immunology (n = 10) ( Table 2) . These publications were cited by 1326 journals. Frontiers in Immunology had the largest number of citations (n = 223), followed by PLoS One (n = 167), the Journal of Immunology (n = 136) and Scientific Reports (n = 82). Research on IL-35 was found to have been conducted in 41 countries. China was the country with the largest number of published papers (n = 202), followed by the USA (n = 91), and Germany ( A total of 50 research field were represented, with the majority of publications focusing on immunology (n = 171), cell biology (n = 65), and biochemistry-molecular biology (n = 60). Figure 2 shows the top 10 research fields in IL-35 papers from 2009 to 2018. The map analysis was shown by a literature co-citation network. The network contains 225 nodes and 446 links. The Modularity Q was 0.8258 (>0.5), meaning that the clusters of networks were reasonable. The Mean Silhouette was 0.5107, indicating that the homogeneity of clusters was, on average, acceptable. As shown in Fig. 3 , nodes represent referenced documents. The largest cluster in the visualization is #0 job profile, followed by #1 antitumor activity, #2 turning promiscuous protein, and #3 IL-12 family cytokine. These clusters were also shown in a timeline view (Fig. 4) . We used CiteSpaceV to analyze keywords. Over a period of time, a knowledge map of the cooccurrence of keywords may reflect hot topics, whereas trending keywords may indicate frontier topics. Generating a visual knowledge map of keyword cooccurrence resulted in 130 nodes and 431 links (Fig. 5) . The strongest citation bursts keywords were as follows: ''central nervous system,'' ''dendritic cell,'' and ''IL-27'' (Fig. 6 ). In this study, we analyzed the structure of the citation network and the trends in topics of recent research involving IL-35. An analysis of the literature published about IL-35 over the past 10 years showed a high growth rate of publications related to IL-35 with frequent citations, indicating that the study of IL-35 was a hot topic. The top 10 institutions that were engaged in IL-35 research contributed to 118 publications, accounting for 28.37% of the total number of research papers. Of the top ten, six institutions were from China. Over the past 10 years, China has been the leading country in IL-35 research, indicating China's great progress in the life sciences. In order to compare the reception of each publication, we also analyzed the citation frequency of the papers. The results showed that an article published in Nature Immunology (Collison et al., 2010) was the most frequently cited article, indicating that ''IL-35-mediated induction of a potent regulatory T cell population'' was an important publication to reference in IL-35 research. The co-citation knowledge map refers to a network of co-citation publications to determine research frontiers. These nodes represent different documents, marked by the year of publication and the author of the publication. The size of the node is proportional to the number of references cited in specific time periods. The red citation ring indicates a sudden increase of citations over a period of time. Trending citations provide an effective way to track research hotspots. Furthermore, we analyzed the characteristics related to clusters of references and constructed a visual map of this research that contained 225 nodes and 446 links. The color of the node indicates how recently the relevant literature had been published. The dark color corresponds to older research, the yellow or orange color to new research (Chen et al., 2012) . Among the 14 clusters, Cluster 0 (job profile) is the largest. The topics of Cluster 1 (antitumor activity), Cluster 2 (turning promiscuous protein), Cluster 4 (emerging role), and Cluster 7 (regulatory B cell) were the newest research . The publications that comprised Cluster 1 (antitumor activity) focused on the role of IL-35 in cancer, including the severity of the malignancy, the clinical stage of the tumor, the promoting of tumor growth, the autocrine growth factor, and the limited antitumor immunity (Zeng et al., 2013; Wang et al., 2013; Nicholl et al., 2014; Turnis et al., 2016) . Cluster 2 (turning promiscuous protein) publications focused on unconventional proteins, including unconventional modes of signaling, and the suppression of autoimmune disease and responsive anti-inflammatory cytokines (Li et al., 2012; Collison et al., 2012; Wang et al., 2014) . The cluster 4 (emerging role) research reported that the low serum level of IL-35 is related to both active systemic lupus erythematosus and active rheumatoid arthritis (Li et al., 2012; Collison et al., 2012; Wang et al., 2014) . Interestingly, some studies reported that IL-35 promotes chronic inflammation (Filková et al., 2015; Thiolat et al., 2014) . The publications corresponding to cluster 7 (regulatory B cell) focused on the function of the regulatory B cell, including inflammation, autoimmunity, and the maintenance of the fine equilibrium required for infectious tolerance (Iwata et al., 2011; Yoshizaki et al., 2012; Mauri & Bosma, 2012; Flores-Borja et al., 2013) . Bursts of keywords provide a reasonable forecasting of the research frontier. Citespace detected several bursts which were regarded as an indicator of the frontiers of IL-35 research. In the Fig. 6 , the blue line represents the time interval. The start to the end of each burst interval is indicated by a red line. Therefore, the top three research frontiers of IL-35 were as follows: (1) ''infectious tolerance'': Infection tolerance is an in vivo process in which tolerance is transferred from one group of lymphocytes to another. In this way, short-term treatment aimed at producing infection tolerance may lead to long-term, self-sustaining immune homeostasis in clinical settings (Kendal & Waldmann, 2010) . IL-35 plays an important role in infection tolerance (Olson, Sullivan & Burlingham, 2013; Tao et al., 2015) . (2) ''autoimmunity'': Studies have found abnormal expression of IL-35 in patients suffering from autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, diabetes mellitus type 1, psoriasis, autoimmune hepatitis, multiple sclerosis, and experimental autoimmune uveitis (Choi et al., 2015; Su et al., 2018) . An autoimmune disease is a pathophysiological state; the immune response directly targets and damages the body's own tissues. (3) ''central nervous system'': Through the study of a mouse model, IL-35 was found to be associated with central nervous system demyelination, autoimmune encephalomyelitis, and the control of host responses following central nervous system viral infection (Zandian et al., 2011; Tirotta et al., 2013; Xie et al., 2016) . A study suggested that the level of IL-35 in patients with neuromyelitis optica spectrum disorders was low. This might be an important biomarker of the severity of neuromyelitis optica spectrum disorders . This study will help researchers understand the trends of IL-35 research. Infectious tolerance and autoimmune diseases may be the latest research frontiers. The molecular biological mechanisms of IL-35 need further exploration. The authors received no funding for this work. The composition and signaling of the IL-35 receptor are unconventional The inhibitory cytokine IL-35 contributes to regulatory T-cell function Epstein-Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin Pro-inflammatory effects of interleukin-35 in rheumatoid arthritis CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells Infectious tolerance: therapeutic potential IL-35 is a novel responsive anti-inflammatory cytokinea new system of categorizing anti-inflammatory cytokines Immune regulatory function of B cells IL-35 promotes pancreas cancer growth through enhancement of proliferation and inhibition of apoptosis: evidence for a role as an autocrine growth factor Interleukin 35: a key mediator of suppression and the propagation of infectious tolerance Role of IL-35 in sublingual allergen immunotherapy IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases Emerging role of IL-35 in inflammatory autoimmune diseases Regulatory T cells-derived IL-35 promotes the growth of adult acute myeloid leukemia blasts Interleukin-35 gene therapy exacerbates experimental rheumatoid arthritis in mice Emerging IL-12 family cytokines in the fight against fungal infections Epstein-Barr virus-induced gene 3 negatively regulates neuroinflammation and T cell activation following coronavirus-induced encephalomyelitis Interleukin-35 limits anti-tumor immunity Interleukin-35 induces regulatory B cells that suppress autoimmune disease Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis IL-12R-β has a protective role in relapsing -remitting experimental autoimmune encephalomyelitis Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions Use of cytokine immunotherapy to block CNS demyelination induced by a recombinant HSV-1 expressing IL-2 Assessing the role of IL-35 in colorectal cancer progression and prognosis Decreased serum IL-27 and IL-35 levels are associated with disease severity in neuromyelitis optica spectrum disorders The authors declare there are no competing interests. • Xulong Cai conceived and designed the experiments, performed the experiments, analyzed the data, contributed reagents/materials/analysis tools, authored or reviewed drafts of the paper, approved the final draft.• Chenrong Zhou performed the experiments, analyzed the data, prepared figures and/or tables, approved the final draft.• Li Zhou performed the experiments, prepared figures and/or tables, approved the final draft.• Qiaolan Xu conceived and designed the experiments, contributed reagents/materials/analysis tools, authored or reviewed drafts of the paper, approved the final draft. The following information was supplied regarding data availability:The raw data is available in the Supplemental File. Supplemental information for this article can be found online at http://dx.doi.org/10.7717/ peerj.7992#supplemental-information.