登革病毒 (DV) 感染造成的臨床症狀包含輕微的登革熱以及嚴重的登革出血熱與登革休克症候群。臨床研究證實登革重症病患血清中所表現的抗發炎細胞激素介白素10 (IL-10) 較登革輕症病患高；然而，登革病毒調控介白素10表現之確切分子機制以及其在病理上的意義目前尚未明瞭。本研究論文證實登革病毒感染人類單核球細胞株THP-1可誘導介白素10以及其下游訊息分子細胞激素訊號抑制分子3 (SOCS3) 的表現。進一步發現登革病毒可藉由蛋白質激酶A (PKA) 活化磷脂酰肌醇3激酶 (PI3K)/蛋白質激酶B (PKB) 進而促使轉錄因子環磷酸腺苷反應元件結合蛋白 (CREB) 磷酸化並且入核轉錄誘導介白素10的產生。實驗室先前研究證實肝醣合成酶激酶3 (GSK-3) 可藉由抑制環磷酸腺苷反應元件结合蛋白活性，以降低介白素10生成。而登革病毒感染後確實可藉由蛋白質激酶A/磷脂酰肌醇3激酶訊息路徑抑制肝醣合成酶激酶3的活性；且利用肝醣合成酶激酶3抑制劑可增加登革病毒所誘導之環磷酸腺苷反應元件結合蛋白磷酸化以及介白素10表現量。然而不僅僅是TLR3非依賴性作用，抑制已知的登革病毒受器包括CD209 (DC-SIGN)、CD29 (integrin β1) 以及CD61 (integrin β3) 並不會影響介白素10生成。除此之外，登革病毒所誘導之介白素10亦可促成登革病毒之複製作用及破壞干擾素γ (IFN-γ) 的訊息傳遞。由上述結果指出，登革病毒感染單核球後可藉由調控蛋白質激酶A/磷脂酰肌醇3激酶/蛋白質激酶B/肝醣合成酶激酶3/環磷酸腺苷反應元件結合蛋白的活性誘導介白素10生成，並可能促成介白素10/細胞激素訊號抑制分子3所媒介之免疫逃脫現象。

Dengue virus (DV)-caused anti-inflammatory cytokine interleukin (IL)-10 production is much higher in patients with severe dengue hemorrhagic fever and dengue shock syndrome than those with mild dengue fever; however, the mechanism underlying IL-10 regulation and its pathological significance remain unclear. Here we show that DV infection significantly increases IL-10-mediated expression of suppressor of cytokine signaling 3 in human monocytic THP-1 cells. In DV-infected cells, activation of cyclic adenosine monophosphate (cAMP) response element-binding (CREB), largely through protein kinase A (PKA)- and phosphoinositide (PI) 3-kinase-regulated manners, determines IL-10 increase. Furthermore, sequential activation of PKA facilitates PI3K/PKB signaling. Notably, DV infection causes glycogen synthase kinase (GSK)-3 inactivation in a PKA/PI3K-regulated manner and inhibiting GSK-3 considerably increases DV-induced IL-10 following CREB activation. However, not only TLR3 independently, blocking the well-known DV receptors, including heparan sulfate, CD209 (DC-SIGN), CD29 (integrin β1), and CD61 (integrin β3), do not inhibit DV-induced IL-10. This study also explore the effects of IL-10 signaling on facilitation of viral replication. These results show a molecular basis of PKA/PI3K/PKB/GSK-3/CREB for DV infection-induced IL-10 production followed by IL-10/SOCS3-mediated advantages for viral replication in monocytes.

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