Fontana Judith M, Mygatt Justin G, Conant Katelyn L, Parsons Chris H, Kaleeba Johnan A R
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Department of Medicine and Microbiology, Stanley S. Scott Cancer Center, Louisiana State University Health Science Center, New Orleans, LA 70112, USA.
J Skin Cancer. 2014;2014:246076. doi: 10.1155/2014/246076. Epub 2014 Feb 17.
KSHV is the etiologic agent for Kaposi's sarcoma (KS), a neoplasm that manifests most aggressively as multifocal lesions on parts of human skin with a propensity for inflammatory reactivity. However, mechanisms that control evolution of KS from a benign hyperplasia to the histologically complex cutaneous lesion remain unknown. In this study, we found that KSHV induces proteomic and morphological changes in melanocytes and melanoma-derived cell lines, accompanied by deregulation of the endogenous anti-inflammatory responses anchored by the MC1-R/ α -MSH signaling axis. We also identified two skin-derived cell lines that displayed differences in ability to support long-term KSHV infection and mapped this dichotomy to differences in (a) NF- κ B activation status, (b) processing and expression of KSHV latency-associated nuclear antigen isoforms putatively associated with the viral lytic cycle, and (c) susceptibility to virus-induced changes in expression of key anti-inflammatory response genes that antagonize NF- κ B, including MC1-R, POMC, TRP-1, and xCT. Viral subversion of molecules that control the balance between latency and lytic replication represents a novel correlate of KSHV pathogenesis and tropism in skin and underscores the potential benefit of harnessing the endogenous anti-inflammatory processes as a therapeutic option for attenuating cutaneous KS and other proinflammatory outcomes of KSHV infection in high-risk individuals.
卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤（KS）的病原体，KS是一种肿瘤，最具侵袭性地表现为人类皮肤部位的多灶性病变，且有炎症反应倾向。然而，控制KS从良性增生演变为组织学上复杂的皮肤病变的机制仍不清楚。在本研究中，我们发现KSHV会诱导黑素细胞和黑色素瘤衍生细胞系发生蛋白质组和形态学变化，同时伴随以黑素皮质素受体1（MC1-R）/α-促黑素（α-MSH）信号轴为基础的内源性抗炎反应失调。我们还鉴定了两种皮肤衍生细胞系，它们在支持KSHV长期感染的能力上存在差异，并将这种差异映射到以下几个方面的差异：（a）核因子κB（NF-κB）激活状态；（b）与病毒裂解周期可能相关的KSHV潜伏相关核抗原异构体的加工和表达；（c）对病毒诱导的关键抗炎反应基因表达变化的敏感性，这些基因可拮抗NF-κB，包括MC1-R、阿黑皮素原（POMC）、酪氨酸酶相关蛋白1（TRP-1）和xCT。控制潜伏期和裂解复制之间平衡的分子的病毒颠覆代表了KSHV在皮肤发病机制和嗜性的一种新关联，并强调了利用内源性抗炎过程作为治疗高危个体皮肤KS和KSHV感染其他促炎结果的潜在益处。
