Staugas R E, Harvey D P, Ferrante A, Nandoskar M, Allison A C
Department of Immunology, Adelaide Children's Hospital, South Australia.
Infect Immun. 1992 Aug;60(8):3162-8. doi: 10.1128/iai.60.8.3162-3168.1992.
Pseudomonas aeruginosa is a dominant pathogen in infection in cystic fibrosis. This bacterium is thought to play a major role in the chronic bronchial infection-induced pathophysiology. Our data showed that whole formalin-fixed heat-killed P. aeruginosa was mitogenic for human lymphocytes and induced production of substantial amounts of tumor necrosis factor alpha (TNF) in peripheral blood mononuclear leukocytes in cultures. Significant amounts of TNF were produced at 10(3) bacteria per 2 x 10(5) mononuclear leukocytes. Treatment of P. aeruginosa with polymixin B did not affect its ability to stimulate TNF production, suggesting that bacterial lipopolysaccharide is not involved. P. aeruginosa, however, did not stimulate production of the T-cell lymphokine lymphotoxin (TNF beta). Exotoxin A, considered to be an important virulence factor produced by P. aeruginosa, did not stimulate either lymphoproliferation or production of TNF. In fact, this toxin, at nontoxic concentrations, was found to depress lymphoproliferation induced by phytohemagglutinin and Staphylococcus aureus and decreased production of TNF, lymphotoxin, and gamma interferon in either lymphocytes or macrophages. This toxin similarly inhibited the production of interleukin-1 beta (IL-1 beta) and IL-1 alpha, but for the inhibition of the latter, 25-fold-less toxin was required than for inhibition of the former. Inhibition of production of TNF was as sensitive as the IL-1 alpha to exotoxin A. The effects of exotoxin A on lymphoproliferation and cytokine production could be neutralized by the addition of anti-exotoxin A antibodies. These results suggest that two mechanisms by which P. aeruginosa could contribute to the chronic bronchial infection-induced pathophysiology are the nonspecific stimulation of TNF and IL-1 and the release of exotoxin A, a toxin which depresses immune responses.
铜绿假单胞菌是囊性纤维化感染中的主要病原体。这种细菌被认为在慢性支气管感染诱导的病理生理学中起主要作用。我们的数据表明，完整的福尔马林固定热灭活铜绿假单胞菌对人淋巴细胞有丝分裂原性，并在培养的外周血单核白细胞中诱导产生大量肿瘤坏死因子α（TNF）。每2×10⁵个单核白细胞中有10³个细菌时可产生大量TNF。用多粘菌素B处理铜绿假单胞菌并不影响其刺激TNF产生的能力，这表明细菌脂多糖不参与其中。然而，铜绿假单胞菌不刺激T细胞淋巴因子淋巴毒素（TNFβ）的产生。外毒素A被认为是铜绿假单胞菌产生的一种重要毒力因子，它既不刺激淋巴细胞增殖也不刺激TNF的产生。事实上，在无毒浓度下，这种毒素被发现可抑制由植物血凝素和金黄色葡萄球菌诱导的淋巴细胞增殖，并降低淋巴细胞或巨噬细胞中TNF、淋巴毒素和γ干扰素的产生。这种毒素同样抑制白细胞介素-1β（IL-1β）和IL-1α的产生，但对于抑制后者，所需毒素比抑制前者少25倍。TNF产生的抑制对外毒素A的敏感性与IL-1α相同。外毒素A对淋巴细胞增殖和细胞因子产生的影响可通过添加抗外毒素A抗体来中和。这些结果表明，铜绿假单胞菌可能导致慢性支气管感染诱导的病理生理学的两种机制是TNF和IL-1的非特异性刺激以及外毒素A的释放，外毒素A是一种抑制免疫反应的毒素。
