幽門螺旋桿菌之熱休克蛋白60可藉由乙型轉化生長因子訊息傳遞路徑抑制週邊血液單核球細胞之增生

Abstract

幽門螺旋桿菌的感染與許多上消化道的疾病相關，像是慢性胃炎、消化性潰瘍、黏膜相關淋巴組織淋巴癌（MALT lymphoma）以及胃癌。感染幽門螺旋桿菌患者若無以抗生素加以治療，將轉變為慢性、持續性感染；而上述疾病的發生責主要起因於該病源菌的慢性感染。 因此幽門螺旋桿菌在胃部造成慢性感染機制是一重要研究課題。 在過去的研究中，許多幽門螺旋桿菌的毒性因子（virulence factors）都曾被報導與該病源菌在胃部的慢性感染相關，像是CagA、VacA等等。然而，並非每一臨床上所分離之菌株都具備這些毒性因子的基因，或能製造具有功能性的蛋白質。因此，造成幽門螺旋桿菌在位部慢性感染真正的機制仍有待探討、釐清。 在另一方面，近年來有許多研究指出，熱休克蛋白60似乎在人體免疫系統抵禦病源菌慢性感染的過程中扮演調節的角色。例如，披衣菌（ C. albicans） 及肺結核桿菌 （ M. tuberculosis) 來源之熱休克蛋白60都曾在老鼠實驗模式中被證實與該病源菌所引發的慢性感染相關。因此我們認為，幽門螺旋桿菌來源之熱休克蛋白60（HpHsp60)可能是幽門螺旋桿菌用以逃脫免疫攻擊，甚或抑制免疫反應的一個重要分子。在本篇研究中，我們利用人類週邊血液單核球（human peripheral blood mononuclear cells, PBMCs）作為研究系統，探討HpHsp60對其活化、增生所造成之影響。研究結果顯示，HpHsp60能夠降低PBMCs之增生、影響細胞激素表現以及造成細胞週期的停滯；透過細胞內FoxP3分子之染色，發現HpHsp60可能是藉由引發調控型T細胞（regulatory T cells） 的增生而造成對PBMCs生長抑制。而HpHsp60則是藉由非傳統之TGF-□訊息傳遞路徑誘發調控型T細胞的產生。根據上述研究結果，我們認為幽門螺旋桿菌來源之熱休克蛋白60能夠藉由誘發調控型T細胞之增生來幫助幽門螺旋桿菌逃脫免疫攻擊，在胃部造成慢性感染。

Helicobacter pylori can lead to variety of upper gastrointestinal disorders such as chronic gastritis, peptic ulcer disease, gastric mucosa- associated lymphoid tissue (MALT) lymphoma and gastric cancer. Without treatment, H. pylori would become chronic infection in almost all of those patients. Although the virulent factors of H. pylori such as CagA, VacA have been demonstrated to play roles in H.pylori colonization and persistent infection, not all the strains isolated form clinic carry those virulent factors. Thus, the universal mechanism of the chronic infection for all stains of this pathogen still is unclear. Maybe, certain factor(s) is involved in this immunosuppressive mechanism, which is necessary to be explored. Interestedly, researchers found that Heat shock protein 60 (Hsp60) seems to be related to the regulation of immune responds in chronic infection disease. Literatures indicated that Hsp60s in C. albicans or M. tuberculosis can induce persistent colonization in the murine experimental model. Therefore, the Hsp60 of H. pylori was considered that it may be an immunosuppressive factor. In this study, we investigated the role of H. pylori Hsp60 (HpHsp60) in immunosuppression. The results showed that the treatment with HpHsp60 to human peripheral blood mononuclear cells (PBMCs) decreased the proliferation rate, changed the cytokine secretion profile, and induce cell cycle arrest. Intracellular FoxP3 staining showed the regulatory T cells were increased after HpHsp60 treatment. Furthermore a TGF-□ signaling pathway is shown to be involved in the generation of HpHsp60-induced Treg cells. Taken together, the treatment of HpHsp60 might generate the regulatory T cells and thus help H. pylori to escape from the attacks evoked by human immune system.