{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:49:57Z","timestamp":1791323397251,"version":"4.3.1"},"reference-count":35,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T00:00:00Z","timestamp":1641427200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"2021 Collaborative R&amp;BD Program of The Food Industry Promotional Agency of Korea.","award":["none"],"award-info":[{"award-number":["none"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The white-rot fungi Ceriporia lacerata is used in bioremediation, such as lignocellulose degradation, in nature. Submerged cultures and extracts of C. lacerata mycelia (CLM) have been reported to contain various active ingredients, including \u03b2-glucan and extracellular polysaccharides, and to exert anti-diabetogenic properties in mice and cell lines. However, the immunostimulatory effects have not yet been reported. This study aimed to identify the immunomodulatory effects, and underlying mechanisms thereof, of submerged cultures of CLM using RAW264.7 macrophages and cyclophosphamide (CTX)-induced immunosuppression in mice. Compared to CTX-induced immunosuppressed mice, the spleen and thymus indexes in mice orally administered CLM were significantly increased; body weight loss was alleviated; and natural killer (NK) cytotoxicity, lymphocyte proliferation, and cytokine (tumor necrosis factor [TNF]-\u03b1, interferon [IFN]-\u03b3, and interleukin [IL]-2) production were elevated in the serum. In RAW264.7 macrophages, treatment with CLM induced phagocytic activity, increased the production of nitric oxide (NO), and promoted mRNA expression of the immunomodulatory cytokines TNF-\u03b1, IFN-\u03b3, IL-1\u03b2, IL-6, IL-10, and IL-12. In addition, CLM increased the inducible NO synthase (iNOS) concentration in macrophages, similar to lipopolysaccharide (LPS) stimulation. Mechanistic studies showed that CLM induced the activation of the NF-\u03baB, PI3k\/Akt, ERK1\/2, and JNK1\/2 pathways. Moreover, the phosphorylation of NF-\u03baB and I\u03baB induced by CLM in RAW264.7 cells was suppressed by specific MAPKs and PI3K inhibitors. Further experiments with a TLR4 inhibitor demonstrated that the production of TNF-\u03b1, IL-1\u03b2, and IL-6 induced by CLM was decreased after TLR4 was blocked. Overall, CLM protected against CTX-induced adverse reactions by enhancing humoral and cellular immune functions, and has potential as an immunomodulatory agent.<\/jats:p>","DOI":"10.3390\/ijms23020597","type":"journal-article","created":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T01:15:26Z","timestamp":1641518126000},"page":"597","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Immune-Enhancing Effect of Submerged Culture of Ceriporia lacerata Mycelia on Cyclophosphamide-Induced Immunosuppressed Mice and the Underlying Mechanisms in Macrophages"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0671-4181","authenticated-orcid":false,"given":"Yong Pil","family":"Hwang","sequence":"first","affiliation":[{"name":"Fisheries Promotion Division, Mokpo 58613, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gi Ho","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 34134, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thi Hoa","family":"Pham","sequence":"additional","affiliation":[{"name":"Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 34134, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi Yeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 34134, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chae Yeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 34134, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Yeon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 34134, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0137-0156","authenticated-orcid":false,"given":"Eun Hee","family":"Han","sequence":"additional","affiliation":[{"name":"Drug & Disease Target Research Team, Division of Bioconvergence Analysis, Korea Basic Science Institute (KBSI), Cheongju 28119, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chul Yung","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju 61452, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Deok","family":"Hwang","sequence":"additional","affiliation":[{"name":"FugenCellTech Co., Ltd., Sangju-si 37272, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunyoung","family":"Ahn","sequence":"additional","affiliation":[{"name":"Bio-R&D Center, FugenBio Co., Ltd., Seoul 06740, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8020-8914","authenticated-orcid":false,"given":"Hye Gwang","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon 34134, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-319-57613-8_1","article-title":"The Role of the Immune System Beyond the Fight Against Infection","volume":"1003","author":"Sattler","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0169-409X(01)00169-7","article-title":"Manipulating the immune system: Humoral versus cell-mediated immunity","volume":"51","author":"McNeela","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s00394-005-0554-y","article-title":"Increased immune response in mice consuming rice bran oil","volume":"44","author":"Sierra","year":"2005","journal-title":"Eur. J. Nutr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.carbpol.2016.01.036","article-title":"A comb-like branched \u03b2-d-glucan produced by a Cordyceps sinensis fungus and its pro-tective effect against cyclophosphamide-induced immunosuppression in mice","volume":"142","author":"Hu","year":"2016","journal-title":"Carbohydr. Polym."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Zhou, X., Dong, Q., Kan, X., Peng, L., Xu, X., Fang, Y., and Yang, J. (2018). Immunomodulatory activity of a novel polysaccharide from Lonicera japonica in immunosuppressed mice induced by cyclophosphamide. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0204152"},{"key":"ref_6","first-page":"125","article-title":"Sweet\u2019s syndrome: An immunologically mediated skin disease?","volume":"72","author":"Hartley","year":"1994","journal-title":"Ann. Allergy"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1093\/mmy\/myx098","article-title":"Experimental sporotrichosis in a cyclophosphamide-induced immunosuppressed mice model","volume":"56","author":"Manente","year":"2017","journal-title":"Med. Mycol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.ejphar.2013.06.006","article-title":"The changes induced by cyclophosphamide in intestinal barrier and microflora in mice","volume":"714","author":"Yang","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S480","DOI":"10.21037\/jtd.2018.01.111","article-title":"Identifying and managing the adverse effects of immune checkpoint blockade","volume":"10","author":"Winer","year":"2018","journal-title":"J. Thorac. Dis."},{"key":"ref_10","first-page":"32","article-title":"Immune Modulation from Five Major Mushrooms: Application to Integrative Oncology","volume":"13","author":"Guggenheim","year":"2014","journal-title":"Integr. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.nutres.2019.12.005","article-title":"Phellinus baumii enhances the immune response in cyclophosphamide-induced immu-nosuppressed mice","volume":"75","author":"Yoo","year":"2020","journal-title":"Nutr. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Shin, M.-R., Lee, J.H., Lee, J.A., Kim, M.J., Park, H.-J., Park, B.W., Seo, S.B., and Roh, S.-S. (2021). Immunomodulatory and anti-inflammatory effects of Phellinus linteus mycelium. BMC Complement. Med. Ther., 21.","DOI":"10.1186\/s12906-021-03441-9"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/1475-2891-13-38","article-title":"Immune-modulatory effects of dietary Yeast Beta-1,3\/1,6-D-glucan","volume":"13","author":"Stier","year":"2014","journal-title":"Nutr. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"673","DOI":"10.3389\/fimmu.2018.00673","article-title":"The Complexity of Fungal \u03b2-Glucan in Health and Disease: Effects on the Mononuclear Phagocyte System","volume":"9","author":"Camilli","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_15","first-page":"335","article-title":"A new species, Ceriporia lacerata, isolated from white-Rotted wood","volume":"86","author":"Suhara","year":"2013","journal-title":"Mycotaxon"},{"key":"ref_16","first-page":"485","article-title":"Biological pretreatment of softwood Pinus densi-flora by three white rot fungi","volume":"45","author":"Lee","year":"2007","journal-title":"J. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1007\/s10068-012-0224-9","article-title":"Hyperglycemic effect of submerged culture extract of Ceriporia lacerata in streptozotocin-induced diabetic rats","volume":"21","author":"Kim","year":"2012","journal-title":"Food Sci. Biotechnol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"145","DOI":"10.11002\/kjfp.2015.22.1.145","article-title":"Hypoglycemic effects of submerged culture of Ceriporia lacerata mycelium","volume":"22","author":"Shin","year":"2015","journal-title":"Korean J. Food Preserv."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"179","DOI":"10.3892\/ijmm.2013.1364","article-title":"Crude extract of Ceriporia lacerata has a protective effect on dexamethasone-induced cytotoxicity in INS-1 cells via the modulation of PI3K\/PKB activity","volume":"32","author":"Kim","year":"2013","journal-title":"Int. J. Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.3746\/jkfn.2017.46.12.1419","article-title":"Effects of Submerged Culture of Ceriporia lacerata Mycelium on High Fat Diet-Induced Diabetic Mice with Insulin Resistance","volume":"46","author":"Choi","year":"2017","journal-title":"J. Korean Soc. Food Sci. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"893","DOI":"10.11002\/kjfp.2015.22.6.893","article-title":"Effect of submerged culture of Ceriporia lacerata mycelium on GLUT4 protein in db\/db mouse","volume":"22","author":"Shin","year":"2015","journal-title":"Korean J. Food Preserv."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1084\/jem.192.2.237","article-title":"Antimicrobial Actions of the Nadph Phagocyte Oxidase and Inducible Nitric Oxide Synthase in Experimental Salmonellosis. I. Effects on Microbial Killing by Activated Peritoneal Macrophages in Vitro","volume":"192","author":"Mastroeni","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1344523","DOI":"10.1080\/16546628.2017.1344523","article-title":"Polysaccharide from wheat bran induces cytokine expression via the toll-like receptor 4-mediated p38 MAPK signaling pathway and prevents cyclo-phosphamide-induced immunosuppression in mice","volume":"61","author":"Shen","year":"2017","journal-title":"Food Nutr. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"48","DOI":"10.15188\/kjopp.2019.02.33.1.48","article-title":"Immunostim-ulatory Effects of Blueberry Yeast Fermented Powder Against Cyclophosphamide-induced Immunosuppressed Model","volume":"33","author":"Jeong","year":"2019","journal-title":"J. Physiol. Pathol. Korean Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/0717-6287-47-15","article-title":"Immune enhancement activities of silk lutein extract from Bombyx mori cocoons","volume":"47","author":"Promphet","year":"2014","journal-title":"Biol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"191","DOI":"10.4110\/in.2011.11.4.191","article-title":"Stimulatory Effect of \u03b2-glucans on Immune Cells","volume":"11","author":"Kim","year":"2011","journal-title":"Immune Netw."},{"key":"ref_27","first-page":"1487","article-title":"New Concepts in Nutraceuticals as Alternative for Pharmaceuticals","volume":"5","author":"Nasri","year":"2014","journal-title":"Int. J. Prev. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1080\/09540105.2016.1272553","article-title":"Alleviation of cyclophosphamide-induced immunosuppression in mice by naturally acetylated hemicellulose from bamboo shavings","volume":"28","author":"Huang","year":"2017","journal-title":"Food Agric. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2659","DOI":"10.1080\/21645515.2015.1082694","article-title":"Effects of Fuzheng Paidu tablet on peripheral blood T lymphocytes, intestinal mucosa T lymphocytes, and immune organs in cyclophosphamide-induced immunosuppressed mice","volume":"11","author":"Miao","year":"2015","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.micinf.2016.10.010","article-title":"IL-2 complex treatment amplifies CD8+ T cell mediated immunity following herpes simplex virus-1 infection","volume":"18","author":"Rajasagi","year":"2016","journal-title":"Microbes Infect."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.jns.2014.02.039","article-title":"Cytokine production profiles in chronic relapsing-remitting experimental autoimmune encephalomyelitis: IFNgamma and TNF-alpha are important participants in the first attack but not in the relapse","volume":"340","author":"Hidaka","year":"2014","journal-title":"J. Neurol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-2776(08)60618-5","article-title":"NF-kappa B and rel proteins in innate immunity","volume":"58","author":"Kopp","year":"1995","journal-title":"Adv. Immunol."},{"key":"ref_33","first-page":"614","article-title":"Molecular mechanisms that influence the macrophage m1-m2 polarization balance","volume":"5","author":"Wang","year":"2014","journal-title":"Front. Im-munol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.intimp.2017.08.030","article-title":"Immune-enhancing effects of polysaccharides extracted from Lilium lancifolium Thunb","volume":"52","author":"Pan","year":"2017","journal-title":"Int. Immunopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Jin, S.W., Lee, G.H., Jang, M.J., Hong, G.E., Kim, J.Y., Park, G.D., Jin, H., Kim, H.S., Choi, J.H., and Choi, C.Y. (2020). Immunomodulatory Activity of Lactococcus lactis GCWB1176 in Cyclophosphamide-Induced Immunosuppression Model. Microorganisms, 8.","DOI":"10.3390\/microorganisms8081175"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/597\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:36:34Z","timestamp":1760362594000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/597"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,6]]},"references-count":35,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijms23020597"],"URL":"https:\/\/doi.org\/10.3390\/ijms23020597","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,6]]}}}