Funk J O, Ernst M, Schönharting M M, Zabel P
Department of Clinical Medicine, Forschungsinstitut Borstel, Germany.
Int J Immunopharmacol. 1995 Dec;17(12):1007-16. doi: 10.1016/0192-0561(95)00096-8.
The methylxanthine derivative pentoxifylline (PTX) is an immunomodulatory agent with incompletely characterized effects on cytokine production. To analyse these effects and to delineate new combination strategies in immunotherapy, we have investigated immunomodulatory properties of PTX in combination with dexamethasone (DEX) or cyclosporin A (CsA). Stimulated human peripheral blood mononuclear cells were treated with clinically relevant concentrations of PTX (12.5-100 micrograms/ml), DEX (0.01-10 microM) or CsA (12.5-50 ng/ml), alone or in combination. With increasing doses of PTX the maximum supernatant titres of tumour necrosis factor (TNF)-alpha, interleukin (IL)-2 and interferon (IFN)-gamma decreased concomitantly, and all cultures co-treated with DEX showed synergism. Release of IL-6 was not consistently altered under PTX treatment. Similarly, PTX and CsA synergistically inhibited the release of IL-2, IFN-gamma and, to a lesser degree, TNF-alpha. Although PTX alone did not significantly reduce lymphoproliferation, both combinations of drugs synergistically inhibited this process. Furthermore, to demonstrate that the key mechanism of PTX-induced effects is an increase in intracellular cyclic adenosine 3':5'-monophosphate (cAMP) levels, identical experiments were performed using dibutyryl-cAMP instead of PTX. In cultures treated with PTX and DEX, expression of different cell receptors was analysed. Expression of IL-2 receptor (IL-2R) was reduced in cultures treated with PTX, and combination with DEX led to further reduction. Expression of intercellular adhesion molecule (ICAM)-1 and of leucocyte function antigen (LFA)-1 alpha was also synergistically reduced, though to a lesser degree. HLA-DR expression remained unchanged. In conclusion, we demonstrate that clinically relevant levels of PTX exert profound immunomodulatory effects in vitro, and that the combined treatment with DEX or CsA has synergistic effects.
甲基黄嘌呤衍生物己酮可可碱（PTX）是一种免疫调节剂，其对细胞因子产生的影响尚未完全明确。为了分析这些影响并确定免疫治疗中的新联合策略，我们研究了PTX与地塞米松（DEX）或环孢素A（CsA）联合使用时的免疫调节特性。用临床相关浓度的PTX（12.5 - 100微克/毫升）、DEX（0.01 - 10微摩尔）或CsA（12.5 - 50纳克/毫升）单独或联合处理刺激后的人外周血单个核细胞。随着PTX剂量的增加，肿瘤坏死因子（TNF）-α、白细胞介素（IL）-2和干扰素（IFN）-γ的最大上清液滴度随之降低，并且所有与DEX联合处理的培养物均显示出协同作用。在PTX处理下，IL-6的释放没有持续改变。同样，PTX和CsA协同抑制IL-2、IFN-γ以及程度较轻的TNF-α的释放。尽管单独使用PTX并没有显著降低淋巴细胞增殖，但两种药物组合均协同抑制了这一过程。此外，为了证明PTX诱导效应的关键机制是细胞内环磷酸腺苷（cAMP）水平的升高，使用二丁酰-cAMP代替PTX进行了相同的实验。在用PTX和DEX处理的培养物中，分析了不同细胞受体的表达。在用PTX处理的培养物中，IL-2受体（IL-2R）的表达降低，与DEX联合使用导致进一步降低。细胞间黏附分子（ICAM）-1和白细胞功能抗原（LFA）-1α的表达也协同降低，尽管程度较轻。HLA-DR的表达保持不变。总之，我们证明临床相关水平的PTX在体外具有显著的免疫调节作用，并且与DEX或CsA联合治疗具有协同作用。
