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

Abstract

Several observations suggest endogenous suppressors of inflammatory mediators are present in human blood. alpha-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-alpha, IL-1 beta, 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-alpha, IL-1 beta, 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-alpha, and IL-1 beta 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.

Post-traumatic immunosuppression is reversed by anti-coagulated salvaged blood transfusion: deductions from studying immune status after knee arthroplasty

“…Simple ex-vivo dilution of whole blood triggers synthesis of inflammatory mediators, including IL-1β and TNF-α [52]. Ca 2+ and Mg 2+ depletion enhances production of IL-6, IL-1β, IL-12p70 and other proinflammatory cytokines [53,54].…”

Expanding the Clinical Indications for α1-Antitrypsin Therapy

“…AAT appears to effectively interfere with inflammatory responses and protect from cell death in an impressive variety of in vivo (Table 1) and in vitro (Table 2) experimental models (3). A noteworthy example includes the blockade of inflammatory cytokine release from human peripheral blood mononuclear cells (PBMC) (4). Specifically, AAT decreases the production of important inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, two prototypical upstream mediators of inflammation.…”

“…The endogenous inhibitor of IL-1 activity, IL-1 receptor antagonist, is upregulated by AAT in human blood cells (5). Similarly, IL-10 levels have been shown to increase by AAT in various experimental conditions (4,(6)(7)(8)(9). When examining the cellular targets of AAT, one finds that these primarily include members of the innate immune system, such as macrophages and neutrophils, as well as B lymphocytes and dendritic cells.…”

Proinflammatory Cytokine Profile in Patients With Different Alpha-1-Antitrypsin Phenotypes

“…Под действием А1АТ снижается экспрессия TNFα, стимулированная IFNγ и другими факторами [15,16] и регулиру-ется передача сигнала рецептором TNFα [17]. Также А1АТ регулирует островоспалительный ответ, снижая продукцию IL-1β, IL-6, IL-8 [18], IL-17 [19]. Молекула А1АТ способна связывать IL-8 с образованием комплекса А1АТ -IL-8, в котором хемокин теряет способность привле-кать нейтрофилы [20].…”