Mytar Bozenna, Wołoszyn Maria, Szatanek Rafał, Baj-Krzyworzeka Monika, Siedlar Maciej, Ruggiero Irena, Wieckiewicz Jerzy, Zembala Marek
Department of Clinical Immunology, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Cracow, Poland.
J Leukoc Biol. 2003 Dec;74(6):1094-101. doi: 10.1189/jlb.0403140. Epub 2003 Aug 21.
Although blood monocytes exhibit significant cytotoxic activity against tumor cells, the function of tumor infiltrating macrophages (TIM) is depressed in cancer patients. This study addresses the question of how the antitumor response of human monocytes, assessed by production of cytokines (tumor necrosis factor alpha, TNF; IL-10; IL-12p40) and cytotoxicity, is altered by exposure to cancer cells. Tumor cell--pre-exposed monocytes restimulated with tumor cells showed significantly decreased production of TNF, IL-12, increased IL-10 (mRNA and release) and inhibition of IL-1 receptor-associated kinase-1 (IRAK-1) expression. This down-regulation of cytokine production was selective, as the response of pre-exposed monocytes to lipopolysaccharide (LPS) was unaffected. Treatment of tumor cell--pre-exposed monocytes with hyaluronidase (HAase) improved their depressed production of TNF, while HAase-treated cancer cells did not cause monocyte dysfunction. The response of hyaluronan (HA)--pre-exposed monocytes to stimulation with tumor cells was also inhibited. Cytotoxic activity of monocytes pretreated with cancer cells was also decreased. This study shows that tumor cells selectively deactivate monocytes and suggests that tumor cell-derived HA by blocking CD44 on monocytes inhibits their antitumor response. These observations may provide some explanation for the depressed function of TIM in human malignancy.
尽管血液单核细胞对肿瘤细胞表现出显著的细胞毒性活性，但肿瘤浸润巨噬细胞（TIM）在癌症患者中的功能却受到抑制。本研究探讨了通过细胞因子（肿瘤坏死因子α、TNF；IL-10；IL-12p40）产生和细胞毒性评估的人类单核细胞抗肿瘤反应如何因暴露于癌细胞而改变。用肿瘤细胞再次刺激预先暴露于肿瘤细胞的单核细胞，结果显示TNF、IL-12的产生显著减少，IL-10（mRNA和释放）增加，且IL-1受体相关激酶-1（IRAK-1）表达受到抑制。细胞因子产生的这种下调是选择性的，因为预先暴露的单核细胞对脂多糖（LPS）的反应未受影响。用透明质酸酶（HAase）处理预先暴露于肿瘤细胞的单核细胞可改善其TNF产生受抑制的情况，而用HAase处理的癌细胞不会导致单核细胞功能障碍。预先暴露于透明质酸（HA）的单核细胞对肿瘤细胞刺激的反应也受到抑制。用癌细胞预处理的单核细胞的细胞毒性活性也降低。本研究表明肿瘤细胞选择性地使单核细胞失活，并提示肿瘤细胞衍生的HA通过阻断单核细胞上的CD44抑制其抗肿瘤反应。这些观察结果可能为人类恶性肿瘤中TIM功能受抑制提供一些解释。
