Abstract：
Tuberculosis caused by Mycobacterium tuberculosis is a leading cause of death globally and a major health concern. In humans, macrophages are the first line invaded by M. tuberculosis. Upon infection, macrophages upregulate cyclooxygenase-2 (COX-2) expression and consequently elevate the formation of PGs, including PGE2 and PGD2. Although the role of proinflammatory PGE2 in M. tuberculosis infection has been reported, the roles of PGJ2 and 15-deoxy-PGJ2 (collectively named J2-PGs), the metabolites of PGD2 with anti-inflammatory features, remain elusive. In this study, we show that M. tuberculosis (H37Rv strain)-conditioned medium stimulates human monocyte-derived macrophages (MDMs) to elevate COX-2 expression along with robust generation of PGJ2, exceeding PGD2 formation, and to a minor extent also of 15-deoxy-PGJ2. Of interest, in M1-MDM phenotypes, PGJ2 and 15-deoxy-PGJ2 decreased M. tuberculosis (H37Rv strain)-conditioned medium-induced COX-2 expression and related PG formation by a negative feedback loop. Moreover, these J2-PGs downregulated the expression of the proinflammatory cytokines IL-6, IL-1β, and IFN-γ, but elevated the anti-inflammatory cytokine IL-10 and the M2 markers arginase-1 and CD163. These anti-inflammatory effects of J2-PGs in M1-MDM correlated with impaired activation of TGF-β-activated kinase 1/NF-κB/MAPK pathways. Finally, we found that J2-PGs regulate COX-2 expression, at least partially, via PGD2 receptor (DP1) and chemoattractant receptor homologue expressed on Th2 cells/DP2 receptors, but independent of the J2-PG receptor peroxisome proliferator-activated receptor-γ. Together, our findings reveal that M. tuberculosis induces COX-2 expression in human M1-MDMs, along with robust formation of J2-PGs that mediates anti-inflammatory effects via a negative feedback loop.
摘要：
由结核分枝杆菌引起的结核病是全球死亡的主要原因，也是主要的健康问题。在人类中,巨噬细胞是结核分枝杆菌入侵的第一线。一旦感染,巨噬细胞上调环氧合酶-2（COX-2）的表达，从而提高PGs的形成，包括PGE2和PGD2。虽然促炎PGE2在结核分枝杆菌感染中的作用已有报道,PGJ2和15-脱氧-PGJ2（统称为J2-PG）的作用，PGD2的代谢产物具有抗炎特性，仍然难以捉摸。在这项研究中,我们显示，结核分枝杆菌（H37Rv株）条件培养基刺激人单核细胞衍生的巨噬细胞（MDMs）提高COX-2的表达随着PGJ2的强大生成，超过PGD2的形成，以及在较小程度上15-脱氧-PGJ2。感兴趣的，在M1-MDM表型中，PGJ2和15-脱氧-PGJ2通过负反馈回路降低了结核分枝杆菌（H37Rv菌株）条件培养基诱导的COX-2表达和相关的PG形成。此外，这些J2-PGs下调促炎细胞因子IL-6，IL-1β的表达，和IFN-γ，但抗炎细胞因子IL-10和M2标志物精氨酸酶-1和CD163升高。M1-MDM中J2-PGs的这些抗炎作用与TGF-β激活的激酶1/NF-κB/MAPK通路的活化受损相关。最后,我们发现J2-PGs调节COX-2的表达，至少部分地,通过在Th2细胞/DP2受体上表达的PGD2受体（DP1）和化学引诱物受体同源物，但与J2-PG受体过氧化物酶体增殖物激活受体γ无关。一起,我们的发现表明，结核分枝杆菌诱导人M1-MDMs中COX-2的表达，以及通过负反馈回路介导抗炎作用的J2-PG的强大形成。
