β2 integrin ICAM-1 adhesion molecule interactions in cutaneous inflammation and tumor promotion
β2 integrin ICAM-1 adhesion molecule interactions in cutaneous inflammation and tumor promotion
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DOI：
10.1093/carcin/19.3.445
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发表时间：
1998-03-01
期刊：
影响因子：
4.7
通讯作者：
Robertson, FM
中科院分区：
文献类型：
--
作者：
Oberyszyn, TM;Conti, CJ;Robertson, FM
β(2)整合素（cd18 / cd11 a、b、c）家族蛋白介导白细胞粘附血管内皮，相关配体细胞间粘附分子-1 （ICAM-1; cd54）与β(2)整合素蛋白相互作用，允许白细胞跨内皮迁移到炎症部位。本研究在senar小鼠背表皮局部应用12- o - tetradecanoylpholol -13-acetate （TPA）引起的小鼠急性皮肤炎症模型和皮肤多阶段癌变模型中检测了这些蛋白的功能。在小鼠背表皮局部应用TPA后24小时，真皮白细胞表达较高水平的β(2)整合素蛋白，而外周血白细胞表达较低水平的β(2)整合素蛋白。在tpa处理的皮肤中，ICAM-1蛋白定位于表皮角质形成细胞和血管内皮以及增殖的乳头状瘤细胞。静脉注射50 μ g抗- β(2)整合素抗体或联合抗icam -1抗体均能显著抑制tpa刺激的真皮中性粒细胞浸润（P < 0.001）和髓过氧化物酶（MPO）活性（P < 0.03）；抗β(2)整合素+ ICAM-1粘附分子抗体P < 0.01)，但对tpa诱导的表皮增生无影响。此外，单独注射抗ICAM-1粘附分子抗体（P < 0.004）或联合注射抗β(2)整合素抗体（P < 0.001）均可显著抑制tpa诱导的表皮角质形成细胞产生7,8-二羟基-2′-脱氧鸟苷（8-OHdG）免疫反应蛋白，β(2)整合素/ICAM-1粘附分子协同调节迁移。在tpa诱导的皮肤炎症期间，真皮内白细胞的保留和功能激活，以及在多阶段癌变过程中形成的乳头状瘤间质组织内白细胞的保留和功能激活。抑制这些受体/配体相互作用的药物可能有助于确定特定细胞群在皮肤炎症和多阶段癌变中的作用，也可能具有抗促进和抗进展药物的潜力。
The beta(2) integrin (CD 18/CD 11 a, b, c) family of proteins mediate adherence of leukocytes to vascular endothelium and the associated ligand, intercellular adhesion molecule-1 (ICAM-1; CD 54), interacts with beta(2) integrin proteins to allow transendothelial migration of leukocytes into sites of inflammation. The present study examines the function of these proteins in a murine model of acute cutaneous inflammation induced following topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to the dorsal epidermis of SENCAR mice and in a model of skin multistage carcinogenesis. At 24 h following topical application of TPA to the dorsal epidermis of mice, dermal leukocytes expressed higher levels of beta(2) integrin protein compared with the lower levels of beta(2) integrin protein expression by peripheral blood leukocytes. ICAM-1 protein was localized to epidermal keratinocytes and vascular endothelium in TPA-treated skin and to proliferating papilloma cells. Intravenous (i.v.) injection of either 50 mu g anti-beta(2) integrin antibody alone or in combination with anti-ICAM-1 antibody significantly inhibited both TPA-stimulated neutrophil infiltration into the dermis (P < 0.001) and myeloperoxidase (MPO) activity (P < 0.03 anti-beta(2) integrin antibody; P < 0.01 anti-beta(2) integrin + ICAM-1 adhesion molecule antibodies), but had no effect on TPA-induced epidermal hyperplasia. In addition, injection of either anti-ICAM-1 adhesion molecule antibody alone (P < 0.004) or in combination with anti-beta(2) integrin antibody (P < 0.001) significantly inhibited TPA-induced production of 7,8-dihydroxy-2'-deoxyguanosine (8-OHdG) immunoreactive proteins by epidermal keratinocytes, beta(2) Integrin/ICAM-1 adhesion molecules work in concert to regulate migration, retention and functional activation of leukocytes within the dermis during TPA-induced skin inflammation and within stromal tissue of papillomas that form during multi-stage carcinogenesis. Agents that inhibit these receptor/ligand interactions may be useful in defining the roles of specific cell populations in cutaneous inflammation and multistage carcinogenesis and may also have potential as antipromoting and anti-progression agents.