Hajishengallis George, Nawar Hesham, Tapping Richard I, Russell Michael W, Connell Terry D
Louisiana State University Health Sciences Center, Department of Microbiology, Immunology, and Parasitology, Center of Excellence in Oral and Craniofacial Biology, 1100 Florida Ave., Box 130, New Orleans 70119, USA.
Infect Immun. 2004 Nov;72(11):6351-8. doi: 10.1128/IAI.72.11.6351-6358.2004.
The type II heat-labile enterotoxins, LT-IIa and LT-IIb, exhibit potent adjuvant properties. However, little is known about their immunomodulatory activities upon interaction with innate immune cells, unlike the widely studied type I enterotoxins that include cholera toxin (CT). We therefore investigated interactions of LT-IIa and LT-IIb with human monocytic THP-1 cells. We found that LT-II enterotoxins were inactive in stimulating cytokine release, whereas CT induced low levels of interleukin-1beta (IL-1beta) and IL-8. However, all three enterotoxins potently regulated cytokine induction in cells activated by bacterial lipopolysaccharide or fimbriae. Induction of proinflammatory (tumor necrosis factor alpha [TNF-alpha]) or chemotactic (IL-8) cytokines was downregulated, whereas induction of cytokines with anti-inflammatory (IL-10) or mucosal adjuvant properties (IL-1beta) was upregulated by the enterotoxins. These effects appeared to depend on their A subunits, because isolated B-pentameric subunits lacked regulatory activity. Enterotoxin-mediated inhibition of proinflammatory cytokine induction in activated cells was partially attributable to synergism for endogenous production of IL-10 and to an IL-10-independent inhibition of nuclear factor kappaB (NF-kappaB) activation. In sharp contrast to the holotoxins, the B pentamers (LT-IIaB and, to a greater extent, LT-IIbB) stimulated cytokine production, suggesting a link between the absence of the A subunit and increased proinflammatory properties. In this regard, the ability of LT-IIbB to activate NF-kappaB and induce TNF-alpha and IL-8 was antagonized by the LT-IIb holotoxin. These findings support distinct immunomodulatory roles for the LT-II holotoxins and their respective B pentamers. Moreover, the anti-inflammatory properties of the holotoxins may serve to suppress innate immunity and promote the survival of the pathogen.
II型热不稳定肠毒素LT-IIa和LT-IIb具有强大的佐剂特性。然而，与广泛研究的I型肠毒素（包括霍乱毒素（CT））不同，对于它们与天然免疫细胞相互作用时的免疫调节活性了解甚少。因此，我们研究了LT-IIa和LT-IIb与人类单核细胞THP-1细胞的相互作用。我们发现LT-II肠毒素在刺激细胞因子释放方面无活性，而CT诱导产生低水平的白细胞介素-1β（IL-1β）和IL-8。然而，所有这三种肠毒素在由细菌脂多糖或菌毛激活的细胞中均能有效调节细胞因子的诱导。促炎细胞因子（肿瘤坏死因子α [TNF-α]）或趋化细胞因子（IL-8）的诱导被下调，而具有抗炎（IL-10）或黏膜佐剂特性（IL-1β）的细胞因子的诱导则被肠毒素上调。这些作用似乎取决于它们的A亚基，因为分离出的B五聚体亚基缺乏调节活性。肠毒素介导的对活化细胞中促炎细胞因子诱导的抑制部分归因于内源性IL-10产生的协同作用以及对核因子κB（NF-κB）激活的不依赖IL-10的抑制。与全毒素形成鲜明对比的是，B五聚体（LT-IIaB，在更大程度上是LT-IIbB）刺激细胞因子产生，这表明A亚基的缺失与促炎特性增加之间存在联系。在这方面，LT-IIb全毒素拮抗了LT-IIbB激活NF-κB以及诱导TNF-α和IL-8的能力。这些发现支持了LT-II全毒素及其各自的B五聚体具有不同的免疫调节作用。此外，全毒素的抗炎特性可能有助于抑制天然免疫并促进病原体的存活。
