Omer F M, Riley E M
Institute of Cell, Animal and Population Biology, University of Edinburgh, Edinburgh, EH9 3JT United Kingdom.
J Exp Med. 1998 Jul 6;188(1):39-48. doi: 10.1084/jem.188.1.39.
We have examined the role of the immunomodulatory cytokine transforming growth factor (TGF)-beta in the resolution and pathology of malaria in BALB/c mice. Circulating levels of TGF-beta, and production of bioactive TGF-beta by splenocytes, were found to be low in lethal infections with Plasmodium berghei. In contrast, resolving infections with P. chabaudi chabaudi or P. yoelii were accompanied by significant TGF-beta production. A causal association between the failure to produce TGF-beta and the severity of malaria infection was demonstrated by treatment of infected mice with neutralizing antibody to TGF-beta, which exacerbated the virulence of P. berghei and transformed a resolving P. chabaudi chabaudi infection into a lethal infection, but had little effect on the course of P. yoelii infection. Parasitemia increased more rapidly in anti-TGF-beta-treated mice but this did not seem to be the explanation for the increased pathology of infection as peak parasitemias were unchanged. Treatment of P. berghei-infected mice with recombinant TGF-beta (rTGF-beta) slowed the rate of parasite proliferation and prolonged their survival from 15 to up to 35 d. rTGF-beta treatment was accompanied by a significant decrease in serum tumor necrosis factor alpha and an increase in interleukin 10. Finally, we present evidence that differences in TGF-beta responses in different malaria infections are due to intrinsic differences between species of malaria parasites in their ability to induce production of TGF-beta. Thus, TGF-beta seems to induce protective immune responses, leading to slower parasite growth, early in infection, and, subsequently, appears to downregulate pathogenic responses late in infection. This duality of effect makes TGF-beta a prime candidate for a major immunomodulatory cytokine associated with successful control of malaria infection.
我们研究了免疫调节细胞因子转化生长因子（TGF）-β在BALB/c小鼠疟疾消退及病理过程中的作用。结果发现，在感染伯氏疟原虫的致死性感染中，循环中TGF-β水平以及脾细胞产生的生物活性TGF-β均较低。相比之下，感染恰氏疟原虫或约氏疟原虫后病情逐渐缓解的过程中，会伴随显著的TGF-β产生。用抗TGF-β中和抗体处理感染小鼠，证明了TGF-β产生不足与疟疾感染严重程度之间存在因果关联，这加剧了伯氏疟原虫的毒力，并将逐渐缓解的恰氏疟原虫感染转变为致死性感染，但对约氏疟原虫感染进程影响不大。抗TGF-β处理的小鼠中寄生虫血症增加得更快，但这似乎并非感染病理加重的原因，因为峰值寄生虫血症并未改变。用重组TGF-β（rTGF-β）处理感染伯氏疟原虫的小鼠，减缓了寄生虫增殖速度，并将其存活时间从15天延长至35天。rTGF-β处理伴随着血清肿瘤坏死因子α显著降低以及白细胞介素10增加。最后，我们提供的证据表明，不同疟疾感染中TGF-β反应的差异是由于疟原虫物种在诱导TGF-β产生能力上的内在差异。因此，TGF-β似乎在感染早期诱导保护性免疫反应，导致寄生虫生长减缓，随后在感染后期似乎下调致病性反应。这种双重作用使TGF-β成为与成功控制疟疾感染相关的主要免疫调节细胞因子的主要候选者。
