Cho Jae Youl, Kim Ae Ra, Joo Hong-Gu, Kim Byung-hun, Rhee Man Hee, Yoo Eun Sook, Katz David R, Chain Benjamin M, Jung Jee H
School of Biotechnology and Bioengineering, Kangwon National University, Chuncheon 200-701, Republic of Korea.
Biochem Biophys Res Commun. 2004 Jan 23;313(4):954-61. doi: 10.1016/j.bbrc.2003.12.026.
Cynaropicrin is a sesquiterpene lactone displaying immunomodulatory effects on the production of cytokine and nitric oxide from macrophages/monocytes. In this study we have examined inhibitory effect of cynaropicrin on activation of major adhesion molecules [CD29 (beta1 integrins), CD43, and CD98] on the cells assessed by U937 (promonocytic cells) homotypic aggregation. Cynaropicrin potently blocked CD29 (beta1 integrins)- and CD98-induced homotypic aggregation with IC(50) values of 3.46 and 2.98 microM, respectively, without displaying cytotoxicity. Similarly, flow cytometric analysis exhibited that cynaropicrin down-regulated strikingly surface level of CD29 and CD147, a functional regulator of CD98, but not CD43. More importantly, cynaropicrin inhibition was linked to blockade of extracellular signal-related kinase (ERK) activation and distinct from other enzyme inhibitors including rottlerin, propranolol, forskolin, and chloroquine, but not cytochalasin B. Therefore, our finding is the first demonstration that cynaropicrin may be a potent functional regulator of CD29 and CD98 via interrupting ERK activation which may be linked to cytoskeleton rearrangement, suggesting further application to CD29- and CD98-mediated diseases such as virus-induced chronic inflammation, and invasion, migration, and metastasis of leukocyte cancer cells.
菜蓟苦素是一种倍半萜内酯，对巨噬细胞/单核细胞产生细胞因子和一氧化氮具有免疫调节作用。在本研究中，我们通过U937（前单核细胞）同型聚集来评估菜蓟苦素对细胞上主要黏附分子[CD29（β1整合素）、CD43和CD98]激活的抑制作用。菜蓟苦素能有效阻断CD29（β1整合素）和CD98诱导的同型聚集，IC50值分别为3.46和2.98 microM，且无细胞毒性。同样，流式细胞术分析表明，菜蓟苦素显著下调CD29和CD147（CD98的功能调节因子）的表面水平，但对CD43无影响。更重要的是，菜蓟苦素的抑制作用与细胞外信号相关激酶（ERK）激活的阻断有关，且不同于包括rottlerin、普萘洛尔、福斯可林和氯喹在内的其他酶抑制剂，但与细胞松弛素B不同。因此，我们的发现首次证明菜蓟苦素可能是CD29和CD98的有效功能调节剂，通过中断ERK激活，这可能与细胞骨架重排有关，提示其在CD29和CD98介导的疾病如病毒诱导的慢性炎症以及白细胞癌细胞的侵袭、迁移和转移等方面有进一步应用。
