半乳糖凝集素-12於人類皮脂細胞發炎反應中所扮演的角色

Abstract

半乳糖凝集素-12(galectin-12)係一種可結合半乳糖苷(β-galactoside)的動物凝集素，具有兩個連結的碳水化合物識別區。它表現在脂肪細胞、白細胞、皮脂細胞且分布在細胞內的脂肪油滴周圍。先前文獻指出galectin-12在脂質代謝中扮演調控的角色。根據我們最近的研究，發現galectin-12藉由調控過氧化物酶體增殖物激活受體γ (peroxisome proliferator-activated receptor-γ)的基因表現而影響皮脂細胞的功能，包括皮脂細胞的分化、增生及脂質生成。此外，在galectin-12基因剔除小鼠中，發現皮脂腺的大小下降。研究也指出皮脂腺和多種皮膚疾病有關，包括異位性皮膚炎(atopic dermatitis，AD)。結合以上所述，我們假設galectin-12可能藉由調控皮脂細胞的功能，進而參與異位性皮膚炎的致病機轉。我們在galectin-12基因剔除小鼠中發現表皮厚度下降、由脾臟細胞製造的輔助型T細胞Th1及Th2 細胞激素的量有下降的趨勢，且這些激素的基因表現量，及肥大細胞的數目在皮膚病灶處也呈現下降現象。以上結果顯示當galectin-12缺失時，老鼠的發炎狀況較輕微，雖然我們觀察到Th2反應和OVA-specific IgE的量反而上升。接下來，我們進一步探討galectin-12在皮脂細胞的發炎反應中所扮演的角色。我們使用RNA干擾 (RNA interference)的方式抑制galectin-12的基因表現，再以脂多醣(LPS) 或痤瘡丙酸桿菌(Propionibacterium acnes) 刺激皮脂細胞，藉以探討galectin-12在皮脂細胞的發炎反應中所扮演的角色，並深入探討可能的機制。結果顯示當皮脂細胞中的galectin-12降低時，IL-1α, TNF-α, IL-6 and IL-8的mRNA表現量及分泌量皆下降。另外，當galectin-12下降時，p-IKKβ, p-IκB, IκB, total NFκB及NFκB移至細胞核的量也下降。綜合以上結果，我們認為galectin-12與AD有關，且在皮脂細胞的發炎反應中扮演調節性的角色。

Galectin-12 is a β-galactoside-binding animal lectin with two carbohydrate recognition domains (CRDs) and a linker sequence. It is expressed in adipocytes, leukocytes and sebocytes and associated with lipid droplets in cells. Previous studies suggested that galectin-12 plays a role in regulating lipid metabolism. Our recent study showed that galectin-12 is also involved in the regulation of sebocyte functions, including sebocyte differentiation, proliferation and lipogenesis by modulating peroxisome proliferator-activated receptor (PPAR)-γ expression. In addition, galectin-12-deficient mice showed a smaller size of sebaceous glands. It has been reported that sebaceous glands are associated with several skin diseases, including atopic dermatitis. Taken together, we hypothesized that galectin-12 may contribute to atopic dermatitis (AD) through regulating sebocyte functions. In AD model, we found a reduced epidermal thickness, slightly lower Th1 and Th2 cytokine production by splenocytes and mRNA expression in skin lesions, decreased numbers of mast cells in galectin-12-deficient mice, indicating the inflammatory status was alleviated in the absence of galectin-12, though the Th2 response and OVA-specific IgE were contradictory elevated. Next, we investigated the role of galectin-12 in regulating sebocyte inflammatory responses, using LPS or Propionibacterium acnes for stimulation after knockdown of galectin-12 by RNA interference and further addressed the underlying mechanism. Results supported that down-regulation of galectin-12 reduced IL-1α, TNF-α, IL-6 and IL-8 at mRNA and protein levels in SZ95 human sebocytes. Moreover, p-IKKβ, p-IκB, IκB, total NFκB levels, and translocation of NFκB to the nucleus were decreased when galectin-12 was down-regulated. We conclude that galectin-12 is involved in the development of AD and plays a regulatory role in the inflammatory responses of sebocytes.