Wu S H, Kelefiotis D P, Lianos E A
Department of Medicine, Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital, Milwaukee.
Immunopharmacology. 1994 Sep-Oct;28(2):125-36. doi: 10.1016/0162-3109(94)90028-0.
In a rat model of glomerular mesangial cell immune injury induced by a monoclonal antibody (ER4) against the mesangial cell membrane antigen Thy 1.1 and in which mesangial cell proliferation is a prominent feature, we examined the role of arachidonate 5- and 12-lipoxygenation (LO) eicosanoids and of thromboxane (Tx) in modulating the proliferative response. Significant increments in glomerular cell proliferation, assessed by counting glomerular cells positive for the Proliferating Cell Nuclear Antigen (PCNA) and by the incorporation of [3H]thymidine ([3H]TdR) in mesangial cell outgrowths from explanted glomeruli, occurred during the mesangioproliferative phase of injury. This event was abrogated in animals depleted of leukocytes or platelets prior to administration of ER4 and in animals pretreated with the arachidonate 5-LO inhibitor MK886. Pretreatment with the Tx synthase inhibitor, Furegrelate, or the arachidonate 12-LO inhibitor, Baicalein, had no effect, indicating that eicosanoids of arachidonate 5-LO but not those of 12-LO or Tx modulate mesangial cell proliferation following immune injury. We further identified those 5-lipoxygenation eicosanoids with growth modulatory effects on cultured mesangial cells. Leukotriene (LT)C4 and D4 but not LTB4 or 5-hydroxyeicosatetraenoic (HETE) acid enhanced [3H]TdR incorporation in growth-arrested mesangial cells. This effect of LTC4 and LTD4 was abrogated by the specific protein kinase C (PKC) inhibitor calphostin C, indicating a PKC-dependent mechanism. LTC4 and LTD4 but not 5-HETE or LTB4 also increased mesangial cell mass levels of the endogenous PKC activator diacylglycerol. The observations indicate that leukocyte-derived arachidonate 5-LO eicosanoids modulate mesangial cell proliferation following immune injury. Of these LTC4 and LTD4 are the likely candidates as they promote mesangial cell growth via a PKC-dependent mechanisms.
在由抗系膜细胞膜抗原Thy 1.1的单克隆抗体（ER4）诱导的肾小球系膜细胞免疫损伤大鼠模型中，系膜细胞增殖是一个突出特征，我们研究了花生四烯酸5-和12-脂氧合（LO）类二十烷酸以及血栓素（Tx）在调节增殖反应中的作用。通过计数增殖细胞核抗原（PCNA）阳性的肾小球细胞以及通过[3H]胸腺嘧啶核苷（[3H]TdR）掺入从移植肾小球长出的系膜细胞中，评估肾小球细胞增殖，在损伤的系膜增生期出现显著增加。在给予ER4之前使白细胞或血小板耗竭的动物以及用花生四烯酸5-LO抑制剂MK886预处理的动物中，这一事件被消除。用Tx合酶抑制剂呋格雷酯或花生四烯酸12-LO抑制剂黄芩苷预处理没有效果，表明花生四烯酸5-LO的类二十烷酸而非12-LO或Tx的类二十烷酸在免疫损伤后调节系膜细胞增殖。我们进一步鉴定了那些对培养的系膜细胞具有生长调节作用的5-脂氧合类二十烷酸。白三烯（LT）C4和D4而非LTB4或5-羟基二十碳四烯酸（HETE）增强了生长停滞的系膜细胞中[3H]TdR的掺入。LTC4和LTD4的这种作用被特异性蛋白激酶C（PKC）抑制剂钙泊三醇C消除，表明是一种依赖PKC的机制。LTC4和LTD4而非5-HETE或LTB4也增加了系膜细胞内源性PKC激活剂二酰甘油的水平。这些观察结果表明，白细胞来源的花生四烯酸5-LO类二十烷酸在免疫损伤后调节系膜细胞增殖。其中LTC4和LTD4可能是候选者，因为它们通过依赖PKC的机制促进系膜细胞生长。
