Department of Biochemistry, Osmania University, Hyderabad 500007, Telangana, India.
Department of Microbiology, Osmania University, Hyderabad 500007, Telangana, India.
Immunol Lett. 2019 Mar;207:17-27. doi: 10.1016/j.imlet.2019.01.002. Epub 2019 Jan 6.
Sepsis is characterized by delayed acute phase response and lowered immune tolerance in patients. Acute phase serum proteins, like Haptoglobin (Hp), have been associated with increased mortality in bacteria mediated acute lung inflammation and sepsis in neonates. However, it's direct role in modulating the immune response by regulating pro-inflammatory mediators leading to immune tolerant state and if gender affects its expression levels during bacterial infection, especially in blood has not been fully explored. To understand its specific role in endotoxin-mediated immune response, we investigated the correlation between the rise in Hp levels on bacterial infection and its influence on the expression of pro-inflammatory mediators in male and female Whole blood (WHB) and PBMCs. Here, we observed pathogen-specific and gender-specific expression of Hp. Gonadal steroid hormones differentially influenced the Hp expression in LPS-induced WHB, where the addition of Estrogen increased Hp expression, with suppression of TNFα, in both genders. Further on evaluating, the influence of Hp on TNFα expression in endotoxin tolerance (ET), we show that increased Hp levels directly reduced TNFα expression in ET models. Interestingly, blockade of secreted Hp significantly reversed the (ET) state, confirmed by a significant rise in TNFα expression in both ex vivo and in vitro ET models, indicating a possible feedback inhibition by Hp on inflammatory mediators like TNFα. We also investigated the role of PKCδ in the regulation of LPS induced secretion of acute phase proteins (Hp) in serum, where inhibition of PKCδ, reduced secretion of anti-microbial proteins in response to LPS shown by restored bacterial growth. These findings clearly highlight the crucial role of Hp in maintaining immune tolerance via suppressing the pro-inflammatory mediators and also in preventing bacterial proliferation in blood during infection.
脓毒症的特征是患者急性期反应延迟和免疫耐受降低。急性期血清蛋白，如触珠蛋白（Hp），与细菌介导的急性肺炎症和新生儿脓毒症中的死亡率增加有关。然而，它在调节免疫反应方面的直接作用，通过调节促炎介质导致免疫耐受状态，以及它在细菌感染期间是否会影响其表达水平，特别是在血液中，尚未得到充分探索。为了了解其在内毒素介导的免疫反应中的特定作用，我们研究了细菌感染时 Hp 水平升高与促炎介质表达之间的相关性，以及其在男性和女性全血（WHB）和 PBMCs 中的影响。在这里，我们观察到 Hp 的病原体特异性和性别特异性表达。性腺类固醇激素对内毒素诱导的 WHB 中 Hp 的表达有不同的影响，其中雌激素的加入增加了 Hp 的表达，同时抑制了 TNFα，在两性中均如此。进一步评估 Hp 对内毒素耐受（ET）中 TNFα表达的影响，我们表明，Hp 水平的升高直接降低了 ET 模型中 TNFα的表达。有趣的是，阻断分泌的 Hp 显著逆转了 ET 状态，这通过在体外和体内 ET 模型中 TNFα表达的显著升高得到证实，表明 Hp 可能对 TNFα等炎症介质存在反馈抑制作用。我们还研究了 PKCδ 在调节 LPS 诱导的血清急性期蛋白（Hp）分泌中的作用，其中 PKCδ 的抑制减少了 LPS 诱导的抗菌蛋白的分泌，表现为细菌生长恢复。这些发现清楚地强调了 Hp 通过抑制促炎介质在维持免疫耐受以及在感染期间防止血液中细菌增殖方面的关键作用。
