Proinflammatory cytokine IL-1β promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors: In vivo analysis of tumor-stromal interaction

Yasuo Saijo, Masashi Tanaka, Makoto Miki, Kazuhiro Usui, Takuji Suzuki, Makoto Maemondo, Xin Hong, Ryushi Tazawa, Toshiaki Kikuchi, Kouji Matsushima, Toshihiro Nukiwa

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185 Citations (Scopus)

Abstract

Inflammatory conditions are associated with tumor development. IL-1β is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1β in tumor growth in vivo, we transduced the retroviral vector coding human IL-1β gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1β) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1β grew faster (240%, day 18, vs null-vector control LLC/neo;p < 0.01) and showed more abundant vasculature (250%, vs LLC/neo; p < 0.05), whereas LLC/IL-1β cells, LLC/neo cells, and wild-type LLC cells did not show any significant difference in the growth rate in vitro. As compared with LLC/neo cells, LLC/IL-1β cells secreted 2-fold the amount of vascular endothelial growth factor and > 10-fold the amount of macrophage-inflammatory protein-2 (CXCL2), one of whose main functions is angiogenesis. Although LLC/IL-1β itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1β cells also contained a >4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1β tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1β cells secreted even larger amounts of vascular endothelial growth factor and macrophage-inflammatory protein-2. The antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor growth of LLC/IL-1β cells in vivo. These results indicated that secreting IL-1β into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.

Original languageEnglish
Pages (from-to)469-475
Number of pages7
JournalJournal of Immunology
Volume169
Issue number1
Publication statusPublished - 2002 Jul 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Saijo, Y., Tanaka, M., Miki, M., Usui, K., Suzuki, T., Maemondo, M., Hong, X., Tazawa, R., Kikuchi, T., Matsushima, K., & Nukiwa, T. (2002). Proinflammatory cytokine IL-1β promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors: In vivo analysis of tumor-stromal interaction. Journal of Immunology, 169(1), 469-475.