Effect of triggering epidermal Fc gamma receptors on the interleukin-2- and interleukin-6-induced upregulation of Ia antigen expression by murine epidermal Langerhans cells: the role of prostaglandins and cAMP.
Effect of triggering epidermal Fc gamma receptors on the interleukin-2- and interleukin-6-induced upregulation of Ia antigen expression by murine epidermal Langerhans cells: the role of prostaglandins and cAMP.
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触发表皮 Fc γ 受体对白细胞介素 2 和白细胞介素 6 诱导的小鼠表皮朗格汉斯细胞 Ia 抗原表达上调的影响：前列腺素和 cAMP 的作用。
DOI：
10.1111/1523-1747.ep12481477
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发表时间：
1991
期刊：
影响因子：
--
通讯作者：
Belsito,DV
中科院分区：
文献类型：
--
作者：
Epstein,SP;Baer,RL;Belsito,DV
在含有白细胞介素-2或白细胞介素-6的培养基中孵育鼠表皮后，Ia+表皮朗格汉斯细胞的密度显著上调（分别为对照的159%和175%）。由于Fcγ受体的触发，兔或人IgG可消除这种精氨酸诱导的上调。相反，人伊加不抑制白细胞介素-2或白细胞介素-6的作用。使用不同同种型的鼠IgG，我们已经证明，所有的亚类都能够抑制奎宁诱导的Ia抗原的增强，虽然IgG 1和IgG 2b必须热聚集才有效。IgG介导的事件依赖于前列腺素的合成，因为它们可以被环氧合酶抑制剂吲哚美辛（10 μg/ml）阻断。与已知的对巨噬细胞的抑制作用相反，PGE_（22）不抑制郎格罕细胞上Ia抗原的上调。此外，这些IgG介导的事件依赖于cAMP的产生，因为它们可以被腺苷酸环化酶抑制剂2 '，5'-双脱氧腺苷（1 mM）阻断。尽管PGD 2和cAMP在这一过程中起着明显的中心作用，但不同同种型IgG对FcγR的触发通过至少两种不同的途径阻断了Ia的上调。与朗格汉斯细胞上FcγRII结合的聚集IgG 1或IgG 2b引起的抑制作用可被磷脂酶A2抑制剂对溴苯酰溴消除。相比之下，由最可能与角质形成细胞上的FcγRI结合的单体IgG 2a或可能与同一FcγRI结合的单体IgG 3引起的抑制作用被蛋白激酶C抑制剂星形孢菌素以及钙调蛋白拮抗剂W7消除。最后，1，2-二辛酰基-rac-甘油，蛋白激酶C的激活剂，模拟Ig介导的事件。基于这些发现，以及使用鼠Fcγ受体I和II的单克隆抗体的研究，我们得出结论，与鼠巨噬细胞中的情况一样，触发表皮FcγRI（最有可能在角质形成细胞上）导致通过Ca++依赖性蛋白激酶C途径产生cAMP，而触发表皮FcγRII（最有可能在朗格汉斯细胞上），通过磷脂酶A2介导的途径导致cAMP升高。与巨噬细胞的情况相反，PGD 2是两种途径中的重要中间体，这可能是因为朗格汉斯细胞仅具有这种前列腺素的受体。触发朗格汉斯细胞上的PGD 2受体可诱导细胞内cAMP的升高，cAMP似乎作为最终信使消除了奎宁诱导的该细胞上Ia抗原的上调。
Following incubation of murine epidermis in medium containing either interleukin-2 or interleukin-6, there is significant upregulation in the density of Ia+epidermal Langerhans cells (to 159% and 175% of control, respectively). This cytokine-induced upregulation is abrogated by either rabbit or human IgG due to triggering of Fcγ receptors. In Contrast, human IgA does not inhibit the effect of interleukin-2 or interleukin-6. Using different isotypes of murine IgG, we have demonstrated that all subclasses are capable of inhibiting the cytokine-induced enhancement of Ia antigen, although IgG1and IgG2bmust be heat aggregated to be effective. The IgG-mediated events are dependent on prostaglandin synthesis because they can be blocked by the cyclooxygenase inhibitor indomethacin, 10 μg/ml. The responsible PG appears to be PGD2in contrast to its known inhibitory effect on macrophages, PGE2does not inhibit the upregulation of Ia antigen on Langerhans cells. In addition, these IgG-mediated events are dependent upon the generation of cAMP because they can be blocked by the adenylate cyclase inhibitor 2',5'-dideoxyadenosine, 1 mM. Despite the apparently central role of PGD2and cAMP in this process, triggering of the FcγR by different isotypes of IgG blocks upregulation of Ia via at least two different pathways. The inhibition caused by aggregated IgG1or IgG2b, which bind to FcγRII on Langerhans cells, is abrogated by para-bromophenacylbromide, an inhibitor of phospholipase A2. In contrast, the inhibition caused by monomeric IgG2a, which binds to FcγRI most likely on keratinocytes, or monomeric IgG3, which probably binds to this same FcγRI, is abrogated by staurosporine, an inhibitor of protein kinase C, as well as by W7, a calmodulin antagonist. Finally, 1,2 dioctanoyl-rac-glycerol, an activator of protein kinase C, mimics the Ig-mediated events. Based on these findings, as well as studies using monoclonal antibodies to the murine Fcγ receptors I and II, we conclude that, as is the case in murine macrophages, triggering of an epidermal FcγRI, most likely on keratinocytes, results in the generation of cAMP via a Ca++-dependent protein kinase C pathway, whereas triggering of an epidermal FcγRII, most likely on Langerhans cells, results in the elevation of cAMP via a phospholipase A2-mediated pathway. In contrast to the situation for macrophages, PGD2is a vital intermediate in both pathways, perhaps because Langerhans cells have receptors for only this prostaglandin. Triggering of the receptor for PGD2on Langerhans cells induces the elevation of intracellular cAMP, which appears to act as the final messenger abrogating the cytokine-induced upregulation of Ia antigen on this cell.