{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:42:20Z","timestamp":1791286940367,"version":"4.1.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2011,3,1]],"date-time":"2011-03-01T00:00:00Z","timestamp":1298937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Inflammatory cytokines modulate immune responses in the tumor microenvironment during progression\/metastasis. In this study, we have assessed the role of IL-1 and IL-17 in the control of antitumor immunity versus progression in a model of experimental lung metastasis, using 3LL and B16 epithelial tumor cells. The absence of IL-1 signaling or its excess in the lung microenvironment (in IL-1\u03b2 and IL-1R antagonist knockout [KO] mice, respectively) resulted in a poor prognosis and reduced T cell activity, compared with WT mice. In IL-1\u03b2 KO mice, enhanced T regulatory cell development\/function, due to a favorable in situ cytokine network and impairment in APC maturation, resulted in suppressed antitumor immunity, whereas in IL-1R antagonist KO mice, enhanced accumulation and activity of myeloid-derived suppressor cells were found. Reduced tumor progression along with improved T cell function was found in IL-17 KO mice, compared with WT mice. In the microenvironment of lung tumors, IL-1 induces IL-17 through recruitment of \u03b3\/\u03b4 T cells and their activation for IL-17 production, with no involvement of Th17 cells. These interactions were specific to the microenvironment of lung tumors, as in intrafootpad tumors in IL-1\/IL-17 KO mice, different patterns of invasiveness were observed and no IL-17 could be locally detected. The results highlight the critical and unique role of IL-1, and cytokines induced by it such as IL-17, in determining the balance between inflammation and antitumor immunity in specific tumor microenvironments. Also, we suggest that intervention in IL-1\/IL-17 production could be therapeutically used to tilt this balance toward enhanced antitumor immunity.<\/jats:p>","DOI":"10.4049\/jimmunol.1002901","type":"journal-article","created":{"date-parts":[[2011,2,8]],"date-time":"2011-02-08T05:34:39Z","timestamp":1297143279000},"page":"3462-3471","source":"Crossref","is-referenced-by-count":116,"title":["Microenvironment-Derived IL-1 and IL-17 Interact in the Control of Lung Metastasis"],"prefix":"10.1093","volume":"186","author":[{"given":"Yaron","family":"Carmi","sequence":"first","affiliation":[{"name":"Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences and National Institute of Biotechnology, Ben-Gurion University of the Negev , Beer-Sheva ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gal","family":"Rinott","sequence":"additional","affiliation":[{"name":"Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences and National Institute of Biotechnology, Ben-Gurion University of the Negev , Beer-Sheva ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahar","family":"Dotan","sequence":"additional","affiliation":[{"name":"Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences and National Institute of Biotechnology, Ben-Gurion University of the Negev , Beer-Sheva ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moshe","family":"Elkabets","sequence":"additional","affiliation":[{"name":"Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences and National Institute of Biotechnology, Ben-Gurion University of the Negev , Beer-Sheva ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peleg","family":"Rider","sequence":"additional","affiliation":[{"name":"Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences and National Institute of Biotechnology, Ben-Gurion University of the Negev , Beer-Sheva ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Voronov","sequence":"additional","affiliation":[{"name":"Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences and National Institute of Biotechnology, Ben-Gurion University of the Negev , Beer-Sheva ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron N","family":"Apte","sequence":"additional","affiliation":[{"name":"Shraga Segal Department of Microbiology and Immunology, Faculty of Health Sciences and National Institute of Biotechnology, Ben-Gurion University of the Negev , Beer-Sheva ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,3,15]]},"reference":[{"key":"2025032411134869000_r1","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.cell.2010.01.025","article-title":"Immunity, inflammation, and cancer","volume":"140","author":"Grivennikov","year":"2010","journal-title":"Cell"},{"key":"2025032411134869000_r2","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/nature07205","article-title":"Cancer-related inflammation","volume":"454","author":"Mantovani","year":"2008","journal-title":"Nature"},{"key":"2025032411134869000_r3","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.gde.2007.12.007","article-title":"Immune surveillance: a balance between protumor and antitumor immunity","volume":"18","author":"Ostrand-Rosenberg","year":"2008","journal-title":"Curr. Opin. Genet. Dev."},{"key":"2025032411134869000_r4","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s10555-010-9223-6","article-title":"Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity","volume":"29","author":"DeNardo","year":"2010","journal-title":"Cancer Metastasis Rev."},{"key":"2025032411134869000_r5","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.coi.2007.02.003","article-title":"Links between innate and cognate tumor immunity","volume":"19","author":"Ghiringhelli","year":"2007","journal-title":"Curr. Opin. Immunol."},{"key":"2025032411134869000_r6","doi-asserted-by":"crossref","first-page":"5904","DOI":"10.1038\/onc.2008.271","article-title":"The tumor microenvironment and its role in promoting tumor growth","volume":"27","author":"Whiteside","year":"2008","journal-title":"Oncogene"},{"key":"2025032411134869000_r7","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0065-230X(08)00007-9","article-title":"Tumor-microenvironment interactions: dangerous liaisons","volume":"100","author":"Witz","year":"2008","journal-title":"Adv. Cancer Res."},{"key":"2025032411134869000_r8","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1146\/annurev.immunol.021908.132612","article-title":"Immunological and inflammatory functions of the interleukin-1 family","volume":"27","author":"Dinarello","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"2025032411134869000_r9","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1111\/j.1600-065X.2008.00615.x","article-title":"Is interleukin-1 a good or bad \u2018guy\u2019 in tumor immunobiology and immunotherapy?","volume":"222","author":"Apte","year":"2008","journal-title":"Immunol. Rev."},{"key":"2025032411134869000_r10","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nri2691","article-title":"The IL-1 family: regulators of immunity","volume":"10","author":"Sims","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"2025032411134869000_r11","doi-asserted-by":"crossref","first-page":"8200","DOI":"10.4049\/jimmunol.175.12.8200","article-title":"CD11b+\/Gr-1+ immature myeloid cells mediate suppression of T cells in mice bearing tumors of IL-1beta-secreting cells","volume":"175","author":"Song","year":"2005","journal-title":"J. Immunol."},{"key":"2025032411134869000_r12","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.ccr.2008.10.011","article-title":"Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice","volume":"14","author":"Tu","year":"2008","journal-title":"Cancer Cell"},{"key":"2025032411134869000_r13","doi-asserted-by":"crossref","first-page":"284","DOI":"10.4049\/jimmunol.176.1.284","article-title":"Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression","volume":"176","author":"Bunt","year":"2006","journal-title":"J. Immunol."},{"key":"2025032411134869000_r14","doi-asserted-by":"crossref","first-page":"977","DOI":"10.4049\/jimmunol.179.2.977","article-title":"Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response","volume":"179","author":"Sinha","year":"2007","journal-title":"J. Immunol."},{"key":"2025032411134869000_r15","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1084\/jem.20080108","article-title":"\u201cRe-educating\u201d tumor-associated macrophages by targeting NF-kappaB","volume":"205","author":"Hagemann","year":"2008","journal-title":"J. Exp. Med."},{"key":"2025032411134869000_r16","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1073\/pnas.0437939100","article-title":"IL-1 is required for tumor invasiveness and angiogenesis","volume":"100","author":"Voronov","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411134869000_r17","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1096\/fj.03-0483fje","article-title":"A continuous delivery system of IL-1 receptor antagonist reduces angiogenesis and inhibits tumor development","volume":"18","author":"Bar","year":"2004","journal-title":"FASEB J."},{"key":"2025032411134869000_r18","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.jconrel.2007.07.015","article-title":"Sustained delivery of IL-1 Ra from biodegradable microspheres reduces the number of murine B16 melanoma lung metastases","volume":"123","author":"Lavi","year":"2007","journal-title":"J. Control. Release"},{"key":"2025032411134869000_r19","doi-asserted-by":"crossref","first-page":"7119","DOI":"10.1073\/pnas.0902745106","article-title":"IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation","volume":"106","author":"Ben-Sasson","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411134869000_r20","doi-asserted-by":"crossref","first-page":"13463","DOI":"10.1073\/pnas.0906988106","article-title":"IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells","volume":"106","author":"Guo","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411134869000_r21","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1146\/annurev.immunol.25.022106.141557","article-title":"IL-17 family cytokines and the expanding diversity of effector T cell lineages","volume":"25","author":"Weaver","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"2025032411134869000_r22","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1146\/annurev.immunol.021908.132710","article-title":"IL-17 and Th17 cells","volume":"27","author":"Korn","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"2025032411134869000_r23","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/ni0407-345","article-title":"T(H)-17 cells in the circle of immunity and autoimmunity","volume":"8","author":"Bettelli","year":"2007","journal-title":"Nat. Immunol."},{"key":"2025032411134869000_r24","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1182\/blood-2008-09-177360","article-title":"Endogenous IL-17 contributes to reduced tumor growth and metastasis","volume":"114","author":"Kryczek","year":"2009","journal-title":"Blood"},{"key":"2025032411134869000_r25","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.4049\/jimmunol.0902574","article-title":"IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells","volume":"184","author":"He","year":"2010","journal-title":"J. Immunol."},{"key":"2025032411134869000_r26","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1002\/eji.200940157","article-title":"Tumor-infiltrating IL-17-producing gammadelta T cells support the progression of tumor via promoting angiogenesis","volume":"40","author":"Wakita","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"2025032411134869000_r27","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1182\/blood.V99.6.2114","article-title":"Interleukin-17 inhibits tumor cell growth by means of a T-cell-dependent mechanism","volume":"99","author":"Benchetrit","year":"2002","journal-title":"Blood"},{"key":"2025032411134869000_r28","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1182\/blood-2009-02-203935","article-title":"Type 17 CD8+ T cells display enhanced antitumor immunity","volume":"114","author":"Hinrichs","year":"2009","journal-title":"Blood"},{"key":"2025032411134869000_r29","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1182\/blood-2009-04-215541","article-title":"Does IL-17 promote tumor growth?","volume":"114","author":"Muranski","year":"2009","journal-title":"Blood"},{"key":"2025032411134869000_r30","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nri2742","article-title":"T(H)17 cells in tumour immunity and immunotherapy","volume":"10","author":"Zou","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"2025032411134869000_r31","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1084\/jem.20060285","article-title":"A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis","volume":"203","author":"Sutton","year":"2006","journal-title":"J. Exp. Med."},{"key":"2025032411134869000_r32","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.chom.2010.01.005","article-title":"Microbial colonization drives expansion of IL-1 receptor 1-expressing and IL-17-producing gamma\/delta T cells","volume":"7","author":"Duan","year":"2010","journal-title":"Cell Host Microbe"},{"key":"2025032411134869000_r33","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.immuni.2009.02.007","article-title":"Critical regulation of early Th17 cell differentiation by interleukin-1 signaling","volume":"30","author":"Chung","year":"2009","journal-title":"Immunity"},{"key":"2025032411134869000_r34","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1084\/jem.187.9.1463","article-title":"Production of mice deficient in genes for interleukin (IL)-1alpha, IL-1beta, IL-1alpha\/beta, and IL-1 receptor antagonist shows that IL-1beta is crucial in turpentine-induced fever development and glucocorticoid secretion","volume":"187","author":"Horai","year":"1998","journal-title":"J. Exp. Med."},{"key":"2025032411134869000_r35","doi-asserted-by":"crossref","first-page":"5986","DOI":"10.1073\/pnas.1035999100","article-title":"IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist","volume":"100","author":"Nakae","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411134869000_r36","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1158\/0008-5472.CAN-06-2956","article-title":"Interleukin-1beta-driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors","volume":"67","author":"Krelin","year":"2007","journal-title":"Cancer Res."},{"key":"2025032411134869000_r37","doi-asserted-by":"crossref","first-page":"4705","DOI":"10.4049\/jimmunol.0901511","article-title":"The role of macrophage-derived IL-1 in induction and maintenance of angiogenesis","volume":"183","author":"Carmi","year":"2009","journal-title":"J. Immunol."},{"key":"2025032411134869000_r38","doi-asserted-by":"crossref","first-page":"4874","DOI":"10.4049\/jimmunol.0803916","article-title":"Host-derived interleukin-1alpha is important in determining the immunogenicity of 3-methylcholantrene tumor cells","volume":"182","author":"Elkabets","year":"2009","journal-title":"J. Immunol."},{"key":"2025032411134869000_r39","doi-asserted-by":"crossref","first-page":"27","DOI":"10.3109\/15476910903405528","article-title":"Effects of IL-1 molecules on growth patterns of 3-MCA-induced cell lines: an interplay between immunogenicity and invasive potential","volume":"7","author":"Voronov","year":"2010","journal-title":"J. Immunotoxicol."},{"key":"2025032411134869000_r40","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.immuni.2006.01.001","article-title":"TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells","volume":"24","author":"Veldhoen","year":"2006","journal-title":"Immunity"},{"key":"2025032411134869000_r41","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1126\/science.1178331","article-title":"Development of monocytes, macrophages, and dendritic cells","volume":"327","author":"Geissmann","year":"2010","journal-title":"Science"},{"key":"2025032411134869000_r42","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.immuni.2009.08.001","article-title":"Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity","volume":"31","author":"Sutton","year":"2009","journal-title":"Immunity"},{"key":"2025032411134869000_r43","doi-asserted-by":"crossref","first-page":"2554","DOI":"10.1182\/blood-2009-11-254607","article-title":"Does IL-17 suppress tumor growth?","volume":"115","author":"Ngiow","year":"2010","journal-title":"Blood"},{"key":"2025032411134869000_r44","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s10555-006-9004-4","article-title":"The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions","volume":"25","author":"Apte","year":"2006","journal-title":"Cancer Metastasis Rev."},{"key":"2025032411134869000_r45","doi-asserted-by":"crossref","first-page":"5598","DOI":"10.4049\/jimmunol.176.9.5598","article-title":"Absence of IL-1 receptor antagonist impaired wound healing along with aberrant NF-kappaB activation and a reciprocal suppression of TGF-beta signal pathway","volume":"176","author":"Ishida","year":"2006","journal-title":"J. Immunol."},{"key":"2025032411134869000_r46","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/nri2506","article-title":"Myeloid-derived suppressor cells as regulators of the immune system","volume":"9","author":"Gabrilovich","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"2025032411134869000_r47","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1111\/j.1600-065X.2008.00602.x","article-title":"Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells","volume":"222","author":"Marigo","year":"2008","journal-title":"Immunol. Rev."},{"key":"2025032411134869000_r48","doi-asserted-by":"crossref","first-page":"4499","DOI":"10.4049\/jimmunol.0802740","article-title":"Myeloid-derived suppressor cells: linking inflammation and cancer","volume":"182","author":"Ostrand-Rosenberg","year":"2009","journal-title":"J. Immunol."},{"key":"2025032411134869000_r49","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.coi.2007.02.001","article-title":"Cancer immunosurveillance, immunoediting and inflammation: independent or interdependent processes?","volume":"19","author":"Bui","year":"2007","journal-title":"Curr. Opin. Immunol."},{"key":"2025032411134869000_r50","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1126\/science.1129139","article-title":"Type, density, and location of immune cells within human colorectal tumors predict clinical outcome","volume":"313","author":"Galon","year":"2006","journal-title":"Science"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/186\/6\/3462\/61695503\/1002901.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/186\/6\/3462\/61695503\/1002901.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T12:10:19Z","timestamp":1743163819000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/186\/6\/3462\/7990069"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,3]]},"references-count":50,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2011,3,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1002901","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2011,3]]},"published":{"date-parts":[[2011,3]]}}}