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. 2001 Feb 27;98(5):2688-93.
doi: 10.1073/pnas.041624998.

Chronic elevation of plasma thioredoxin: inhibition of chemotaxis and curtailment of life expectancy in AIDS (V体育官网)

H Nakamura  1 , S C De Rosa, J Yodoi, A Holmgren, P Ghezzi, L A Herzenberg, L A Herzenberg
Affiliations

"VSports注册入口" Chronic elevation of plasma thioredoxin: inhibition of chemotaxis and curtailment of life expectancy in AIDS

H Nakamura et al. Proc Natl Acad Sci U S A. .

VSports - Abstract

Thioredoxin (Trx) is an intracellular redox protein with extracellular cytokine-like and chemokine-like activities. We show here that, although plasma Trx levels are unrelated to survival of HIV-infected individuals with CD4 cell counts above 200/microl blood, survival is significantly impaired (P = 0. 003) when plasma Trx is chronically elevated in HIV-infected subjects with CD4 T cell counts below this level (i. e. , with Centers for Disease Control (CDC)-defined AIDS). Relevant to the mechanism potentially underlying this finding, we also present data from experimental studies in mice showing that elevated plasma Trx efficiently blocks lipopolysaccharide (LPS)-induced chemotaxis, an innate immune mechanism that is particularly crucial when adaptive immunity is compromised VSports手机版. Thus, we propose that elevated plasma Trx in HIV-infected individuals with low CD4 T cell counts directly impairs survival by blocking pathogen-induced chemotaxis, effectively eliminating the last (innate) barrier against establishment of opportunistic and other infections in these immunodeficient individuals. .

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Figures

Figure 1
Figure 1
HIV-infected subjects have elevated plasma thioredoxin levels. Estimated distributions (based on histograms) showing relative numbers of subjects as a function of plasma thioredoxin levels: HIV-negative controls (Top, n = 46); HIV-infected individuals with CD4 cell counts (Middle, n = 102); HIV-infected individuals with CD4 cell counts <200l (Bottom, n = 71). The vertical thin solid line on each histogram shows the median plasma Trx for the indicated group. The dotted vertical line, which is drawn at the 95th percentile for plasma Trx uninfected control subjects (30 ng/ml), is the threshold used to separate normal and elevated Trx levels in this study.
Figure 2
Figure 2
Survival is impaired in HIV-infected subjects with low CD4 T cell counts and elevated plasma Trx. Kaplan-Meier survival analysis for HIV-infected individuals with CD4 cell counts less than 200/μl (n = 71). Log rank P value is shown in the figure; Wilcoxon P value = 0.002. Data are shown for all subjects in the study. When six apparently healthy subjects who had clinical laboratory values outside the acceptable range for the NAC clinical trial were excluded, Log rank P = 0.003 and Wilcoxon P = 0.01.
Figure 3
Figure 3
NAC blocks thioredoxin release in vitro. The HTLV-I-transformed T cell line, ATL-2, was cultured in RPMI 1640 + 10% FCS in the presence of the indicated amount of NAC for 24 hr. Trx levels in the supernatants were measured by ELISA. Ten millimolar NAC is not toxic to these cells. Data shown are representative of three similar experiments.
Figure 4
Figure 4
Circulating thioredoxin blocks local chemotaxis in mice. Recombinant (human) thioredoxin (40 μg) or saline was injected intravenously into mice prepared for the air pouch chemotaxis (9). Within 10 min, LPS (1 μg) was injected into the air pouch on all animals, and leukocyte infiltration into the pouch was measured 4 hr later. Although the ratio between neutrophils and lymphocytes can vary, this experiment has been repeated several times with similar results (decreased recruitment of total cells into the air pouch and decreased ratio of neutrophils to lymphocytes when Trx is injected intravenously).
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