Satish Latha, Yager Dorne, Wells Alan
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
J Invest Dermatol. 2003 Jun;120(6):1110-7. doi: 10.1046/j.1523-1747.2003.12230.x.
Normal wound healing is a complex, highly regulated dynamic process that requires co-ordinate responses of both epidermal and dermal compartments. To accomplish the healing process several growth factors, chemokines, and matrix elements signal both cell proliferation and migration during the inflammatory and reparative phases and limit these responses during the remodeling phase. We have found that the Glu-Leu-Arg-negative CXC chemokines interferon gamma inducible protein 10, monokine induced by interferon gamma, and platelet factor 4, limit fibroblast responsiveness to growth factors, but the functioning of these factors in wound healing remains uncertain. We hypothesized that the keratinocyte-derived member of this Glu-Leu-Arg-negative CXC family, interferon gamma inducible protein 9 (IP-9) CXCL11 (also known as I-TAC, beta-R1, and H-174) signals to the dermal compartment to synchronize the re-epithelialization process. Interferon gamma inducible protein 9 was produced after mechanical wounding of a keratinocyte monolayer, suggesting for the first time that this could be a wound response factor. Interferon gamma inducible protein 9 limited epidermal growth factor (EGF)-induced fibroblast motility (57+/-7%) by the same protein kinase A (KA)-mediated inhibition of calpain activation and cell de-adhesion as described for interferon gamma inducible protein 10. Surprisingly, interferon gamma inducible protein 9 enhanced growth factor-induced motility in undifferentiated keratinocytes (137+/-19%) as determined in a two-dimensional in vitro wound healing assay, and interferon gamma inducible protein 9 alone promoted motility in undifferentiated keratinocytes (49+/-10% of epidermal growth factor-induced motility). A stimulated keratinocyte/target cell coculture system revealed that interferon gamma inducible protein 9 acts as a soluble keratinocyte-derived paracrine factor for both fibroblasts and keratinocytes. Further, we found that in both fibroblasts and undifferentiated keratinocytes, interferon gamma inducible protein 9 exerted its action through modulation of a cytosolic protease, calpain. Interestingly, interferon gamma inducible protein 9 increased calpain activity in undifferentiated keratinocytes, whereas the same chemokine inhibited the calpain activity in fibroblasts. This provides for a model whereby redifferentiated basal keratinocytes could limit fibroblast repopulation of the dermis underlying healed wounds while simultaneously promoting re-epithelialization of the remaining provisional wound.
正常伤口愈合是一个复杂、高度调控的动态过程，需要表皮和真皮层的协调反应。为完成愈合过程，多种生长因子、趋化因子和基质成分在炎症和修复阶段对细胞增殖和迁移发出信号，并在重塑阶段限制这些反应。我们发现，谷氨酸 - 亮氨酸 - 精氨酸阴性的CXC趋化因子，即γ-干扰素诱导蛋白10、γ-干扰素诱导单核因子和血小板因子4，会限制成纤维细胞对生长因子的反应，但这些因子在伤口愈合中的作用仍不确定。我们推测，这个谷氨酸 - 亮氨酸 - 精氨酸阴性的CXC家族中由角质形成细胞衍生的成员，即γ-干扰素诱导蛋白9（IP - 9）CXCL11（也称为I - TAC、β - R1和H - 174），会向真皮层发出信号，以使重新上皮化过程同步。在角质形成细胞单层受到机械损伤后会产生γ-干扰素诱导蛋白9，这首次表明它可能是一种伤口反应因子。γ-干扰素诱导蛋白9通过与γ-干扰素诱导蛋白10相同的蛋白激酶A（PKA）介导的抑制钙蛋白酶激活和细胞去黏附作用，限制表皮生长因子（EGF）诱导的成纤维细胞运动（57±7%）。令人惊讶的是，在二维体外伤口愈合试验中，γ-干扰素诱导蛋白9增强了未分化角质形成细胞中生长因子诱导的运动（137±19%），并且γ-干扰素诱导蛋白9单独就能促进未分化角质形成细胞的运动（为表皮生长因子诱导运动的49±10%）。一个受刺激的角质形成细胞/靶细胞共培养系统显示，γ-干扰素诱导蛋白9作为一种可溶性的角质形成细胞衍生的旁分泌因子，对成纤维细胞和角质形成细胞都起作用。此外，我们发现，在成纤维细胞和未分化角质形成细胞中，γ-干扰素诱导蛋白9都通过调节一种胞质蛋白酶钙蛋白酶发挥作用。有趣的是，γ-干扰素诱导蛋白9增加未分化角质形成细胞中的钙蛋白酶活性，而相同的趋化因子抑制成纤维细胞中的钙蛋白酶活性。这提供了一个模型，即重新分化的基底角质形成细胞可以限制愈合伤口下方真皮中成纤维细胞的再填充，同时促进剩余临时伤口的重新上皮化。
