Ultraviolet B radiation-induced cell death: Critical role of ultraviolet dose in inflammation and lupus autoantigen redistribution
Ultraviolet B radiation-induced cell death: Critical role of ultraviolet dose in inflammation and lupus autoantigen redistribution
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DOI：
10.4049/jimmunol.171.11.5778
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发表时间：
2003-12-01
影响因子：
4.4
通讯作者：
Cohen, PL
中科院分区：
文献类型：
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作者：
Caricchio, R;McPhie, L;Cohen, PL
系统性红斑狼疮中靶向的核自身抗原转移到紫外线照射的凋亡角质形成细胞的细胞膜上，可能是自我免疫的重要来源。很难理解伴随大多数凋亡的非炎症环境如何引起导致自身抗体的免疫原性应答。我们已经发现，角质形成细胞UV暴露的精确量在确定细胞凋亡率、炎性细胞因子产生量和自身抗原易位程度方面至关重要。低剂量的UVB（小于或等于15 mJ/cm 2）可迅速诱导正常的半胱天冬酶依赖性细胞凋亡，而中等剂量的UV-B（35 mJ/cm 2）可导致细胞凋亡，并伴有形态学改变、DNA断裂减慢和多聚（ADP-核糖）聚合酶降解以及Bcl-2增加。高剂量UVB（80 mJ/cm ~ 2）则引起坏死。我们观察到IL-1的生产后，中间和高UVB剂量。核银再分布也显着的UV剂量依赖性：在低剂量下，Sm，Ku，和DNA易位到早期凋亡细胞的表面。在中等剂量下，当细胞核仍然可见时，这些Ag集中在细胞膜上。在高剂量下，这些自身抗原扩散到细胞质中并释放到上清液中。加在一起，结果表明，低剂量UVB诱导迅速的非炎性细胞凋亡。相反，中等和高剂量的UVB诱导促炎性细胞凋亡和坏死，其中炎性细胞因子的产生伴随着自身抗原的暴露和释放。紫外线剂量对凋亡角质形成细胞的命运及其潜在的免疫原性的关键重要性，应有助于澄清UVB在诱导系统性红斑狼疮自身免疫中的作用。
The nuclear self-Ags targeted in systemic lupus erythematosus translocate to the cell membrane of UV-irradiated apoptotic keratinocytes and may represent an important source of self-immunization. It is hard to understand how the noninflammatory milieu accompanying most apoptosis might provoke an immunogenic response leading to autoantibodies. We have found that the precise amount of keratinocyte UV exposure is crucial in determining the rate of apoptosis, the amount of inflammatory cytokine production, and the degree of autoantigen translocation. Low doses of UVB (less than or equal to 15 mJ/cm(2)) promptly induced a normal, caspase-dependent apoptosis, while intermediate doses of UV-B (35 mJ/cm(2)) caused apoptosis with altered morphology, slower DNA fragmentation, and poly(ADP-ribose) polymerase degradation accompanied by increased Bcl-2. High doses of UVB (80 mJ/cm(2)) induced instead necrosis. We observed IL-1 production upon intermediate and high UVB doses. Nuclear Ag redistribution was also markedly UV dose dependent: at low doses, Sm, Ku, and DNA translocated to the surfaces of early apoptotic cells. At intermediate doses, these Ags concentrated on the cell membrane when the nucleus was still visible. At high doses, these autoantigens diffused into the cytoplasm and were released into the, supernatant. Taken together,. the results show that low-dose UVB induces prompt noninflammatory apoptosis. In contrast, intermediate and high doses of UVB induce proinflammatory apoptosis and necrosis, where the production of inflammatory cytokines is accompanied by exposure and release of autoantigens. The key importance of the UV dose on the fate of apoptotic keratinocytes and on their potential immunogenicity should help clarify the role of UVB in inducing systemic lupus erythematosus autoimmunity.