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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901735v1 184/7/3946    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Kim, G.-Y. Articles by Kim, J.-H. PubMed PubMed Citation Articles by Kim, G.-Y. Articles by Kim, J.-H.

Proinflammatory Cytokine IL-1β Stimulates IL-8 Synthesis in Mast Cells via a Leukotriene B₄ Receptor 2-Linked Pathway, Contributing to Angiogenesis

Geun-Young Kim,^* Jin-Wook Lee,^* Ho-Cheol Ryu,^* Jun-Dong Wei,^* Chu-Myong Seong, and Jae-Hong Kim^*

^*School of Life Sciences and Biotechnology, Korea University; and Division of Hematology-Oncology, Department of Internal Medicine, School of Medicine, Ewha Womans University, Seoul, Korea

Recent studies have suggested that mast cells have critical roles in angiogenesis. However, the detailed mechanism by which mast cells contribute to angiogenesis is not yet clearly understood, especially in response to proinflammatory cytokines. In this study, we showed that the proinflammatory cytokine IL-1β induces the synthesis of IL-8, a potent angiogenic factor, in human mast cells via the leukotriene B₄ receptor (BLT)2. We also characterized the BLT2 downstream signaling pathway and determined that BLT2-mediated IL-8 synthesis involves the upregulation of Nox1, a member of the NADPH oxidase family, Nox1-dependent reactive oxygen species generation and the subsequent activation of the redox-sensitive transcription factor NF-B. For instance, knockdown of BLT2 and Nox1 with specific small interfering RNA, treatment with a specific BLT2 antagonist, LY255283, or treatment with a potential Nox inhibitor, diphenylene iodonium, suppressed IL-1β–induced IL-8 synthesis. We found that the conditioned media collected from IL-1β–treated human mast cell line HMC-1 had significantly enhanced angiogenic activity that could be dramatically attenuated by either small interfering RNA knockdown of BLT2 or treatment with neutralizing Ab to IL-8. Finally, the experiments were repeated using human primary cord blood-derived mast cells, and the results were clearly reproduced. Taken together, our results suggest that BLT2-Nox1-reactive oxygen species–dependent pathway plays a role in promoting the secretion of IL-8 from human mast cells in response to the proinflammatory cytokine IL-1β, thus contributing to angiogenesis.

Address correspondence and reprint requests to Dr. Jae-Hong Kim, School of Life Sciences and Biotechnology, Korea University, 5-1 Anam-dong, Sungbuk-gu, Seoul 136-701, Korea. E-mail address: jhongkim{at}korea.ac.kr

This work was supported by the Diseases Network Research Program and the Korea Research Foundation Grant funded by the Korean Government (Basic Research Promotion Fund) (KRF-2008-313-C00603).

The online version of this article contains supplemental material.

Abbreviations used in this paper:

Ang-1, angiopoietin-1; BLT, leukotriene B₄ receptor; COX, cyclooxygenase; cysLT, leukotriene; DCF, dichlorofluorescin; DCFDA, 2,7-dichlorofluorescin diacetate; DPI, diphenylene iodonium; IKK, IB kinase; LO, lipoxygenase; LT, leukotriene; NAC, N-acetylcysteine; Nox, NADPH oxidase; PKC, protein kinase C; ROS, reactive oxygen species; SCF, stem cell factor; scr, scrambled; siRNA, small interfering RNA; VEGF, vascular endothelial growth factor.