Published online before print February 5, 2009

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(Journal of Leukocyte Biology. 2009;85:886-895.)
© 2009 Society for Leukocyte Biology

-1-Antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood

Gregory B. Pott^*,, Edward D. Chan^*,,, Charles A. Dinarello and Leland Shapiro^*,,1

^* Denver Veterans Affairs Medical Center,
University of Colorado Denver, and
National Jewish Medical and Research Center, Denver, Colorado, USA

¹ Correspondence: Denver Veterans Affairs Medical Center and Department of Medicine, Division of Infectious Diseases, University of Colorado Denver, 12700 E. 19th Ave., Box B168, Aurora, CO 80045, USA. E-mail: leland.shapiro{at}uchsc.edu

ABSTRACT

Several observations suggest endogenous suppressors of inflammatory mediators are present in human blood. -1-Antitrypsin (AAT) is the most abundant serine protease inhibitor in blood, and AAT possesses anti-inflammatory activity in vitro and in vivo. Here, we show that in vitro stimulation of whole blood from persons with a genetic AAT deficiency resulted in enhanced cytokine production compared with blood from healthy subjects. Using whole blood from healthy subjects, dilution of blood with RPMI tissue-culture medium, followed by incubation for 18 h, increased spontaneous production of IL-8, TNF-, IL-1β, and IL-1R antagonist (IL-1Ra) significantly, compared with undiluted blood. Dilution-induced cytokine production suggested the presence of one or more circulating inhibitors of cytokine synthesis present in blood. Serially diluting blood with tissue-culture medium in the presence of cytokine stimulation with heat-killed Staphylococcus epidermidis (S. epi) resulted in 1.2- to 55-fold increases in cytokine production compared with S. epi stimulation alone. Diluting blood with autologous plasma did not increase the production of IL-8, TNF-, IL-1β, or IL-1Ra, suggesting that the endogenous, inhibitory activity of blood resided in plasma. In whole blood, diluted and stimulated with S. epi, exogenous AAT inhibited IL-8, IL-6, TNF-, and IL-1β significantly but did not suppress induction of the anti-inflammatory cytokines IL-1Ra and IL-10. These ex vivo and in vitro observations suggest that endogenous AAT in blood contributes to the suppression of proinflammatory cytokine synthesis.

Key Words: inflammation • dilution • serine protease inhibitor • interleukin

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