title: IL-6 Mediates Macrophage Infiltration after Irradiation via Up-regulation of CCL2/CCL5 in Non-small Cell Lung Cancer.
abstract: Radiotherapy is effective in reducing primary tumors, however, it may enhance macrophage infiltration to tumor sites, accelerating tumor progression in several ways. We investigated whether radiation can increase macrophage infiltration into non-small cell lung carcinoma (NSCLC) cells. Analysis of in vitro macrophage (differentiated THP-1 cells) migration to either nonirradiated or irradiated tumor cells showed increased migration to the irradiated tumor cells. Because the IL-6 levels in A549 and H157 cells were significantly increased after irradiation, we then investigated whether this increased IL-6 level contributes to radiation-induced macrophage migration. Radiation-induced macrophage infiltration was reduced when IL-6 was knocked down in tumor cells, indicating a positive IL-6 role in this process. To validate this in vitro result, an orthotopic mouse model was developed using a luciferase-tagged H157siIL-6/scramble control (sc) cell set. After tumors developed, the lungs were irradiated, and infiltration of endogenous macrophages and tail-vein injected fluorescent macrophages to tumor sites was investigated. In both groups, increased macrophage infiltration was observed in H157sc cell-derived xenografts compared to H157siIL-6 cell-derived xenografts, confirming the positive IL-6 role in the radiation-induced macrophage infiltration process. In mechanistic dissection studies, radiation-induced up-regulation of CCL2 and CCL5 by IL-6 was detected, and blocking the action of CCL2/CCL5 molecules significantly reduced the number of migrated macrophages to tumor cells after irradiation. These results demonstrate that targeting the IL-6 signaling or CCL2/CCL5 molecules in combination with conventional radiotherapy potentially blocks undesired radiation-induced macrophage infiltration.
authors.affiliation: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tsai
authors.affiliation: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Kuang-Hsiang
authors.initials: KH
authors.lastname: Chuang
authors.affiliation: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Keng
authors.affiliation: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Soo Ok
authors.initials: SO
authors.lastname: Lee
authors.affiliation: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642.
authors.forename: Yuhchyau
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D002465:Cell Movement / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic; D018932:Chemokine CCL2 / Q000235:genetics*; D018946:Chemokine CCL5 / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000276:immunology* / Q000528:radiation effects; D051379:Mice; D015398:Signal Transduction / Q000528:radiation effects; D015854:Up-Regulation / Q000528:radiation effects*
chemical_list: D018932:Chemokine CCL2; D018946:Chemokine CCL5; D015850:Interleukin-6