Chloroquine attenuates hemorrhagic shock-induced suppression of Kupffer cell antigen presentation and major histocompatibility complex class II antigen expression through blockade of tumor necrosis factor and prostaglandin release

Abstract

Hemorrhagic shock suppresses the ability of Kupffer cells (KC) to present antigen and express the major histocompatibility complex class II (Ia) antigen. These alterations are concomitant with an enhanced release of cytokines (tumor necrosis factor [TNF], interleukin-1 [IL- 1], IL-6) and prostaglandin E2 (PGE2) by KC after hemorrhagic shock. The aim of this study was to determine whether chloroquine (CQ) administration in vivo before or after hemorrhage affects the altered cytokine and PGE2 release by KC as well as the capacity of KC to present antigen and express Ia. To study this, C3H/HeN mice were bled to and maintained at a mean arterial blood pressure of 35 mm Hg for 60 minutes, followed by fluid resuscitation. Chloroquine (10 mg/kg body weight) was injected intramuscularly 2 hours before or during resuscitation following shock. The administration of CQ led to a significant reduction in the hemorrhage-induced elevation of TNF, IL-6, and PGE2 release by KC; however, IL-1 secretion was not affected by CQ. In addition, CQ treatment abolished the hemorrhage-induced increase in circulating TNF and IL-6. These changes in cytokine and PGE2 release following CQ administration correlated with a significant enhancement of the antigen-presenting capacity of KC. No differences were observed between pretreatment and posttreatment with CQ. Our data indicate that CQ selectively inhibits the release of TNF, IL-6, and PGE2 by KC, while IL-1 secretion was unaffected. Because the reduction of these inflammatory mediators was concomitant with a significant improvement of KC capacity to present antigen and express Ia, we propose that TNF, IL-6, and PGE2 play a pivotal role in the induction of posthemorrhage immunosuppression. Furthermore, the data suggest that the suppression of KC functions occurs during or after resuscitation, because posttreatment with CQ was as effective as pretreatment. Additional studies indicated that the survival of animals after hemorrhage and sepsis was significantly increased by posttreatment of hemorrhaged mice with CQ. Thus, CQ, because of its unique ability to selectively inhibit the release of inflammatory cytokines and prostaglandins, represents a potent immunomodulating agent in the treatment of conditions associated with increased cytokine release and for decreasing the mortality from sepsis after hemorrhage.

Chloroquine Enhances the Number of IL‐10 Producing Cells and the Expression of B7‐2 and ICAM‐1 in In Vitro‐Cultured PBMC

“…The characteristics of these cells are lack of expression of pro‐inflammatory molecules (TNF‐α, IL‐6, IL‐12 and the macrophage inflammatory protein (MIP)‐α) and increased expression of anti‐inflammatory molecules (IL‐10, and prostaglandin E 2 [PGE 2 ]) [43]. In line with this, others have shown that chloroquine also suppresses the production of inflammatory molecules [11–16] and our data show increased expression of the anti‐inflammatory cytokine IL‐10. Which cell produces IL‐10 in our system is not clear.…”

“…severe anaemia [6, 7] and cerebral malaria [8–10]. Previous studies have shown that chloroquine inhibits the production of pro‐inflammatory cytokines such as TNF‐α, interferon (IFN)‐γ and interleukin (IL)‐6 [11–16].…”

Male sex steroids are responsible for depressing macrophage immune function after trauma-hemorrhage

“…IL-1 release by peritoneal and splenic macrophages was determined by adding serial dilutions of the supernatants to D10.G4.1 cells (2 ϫ 10 4 cells/well) in the presence of concanavalin A (2.5 µg/ml; Pharmacia, Piscataway, NJ) as previously described (8). Proliferation of the D10.G4.1 cells was measured by [ 3 H]thymidine incorporation.…”

Inhibition of Cathepsin S Reduces Allogeneic T Cell Priming but Not Graft-versus-Host Disease Against Minor Histocompatibility Antigens

“…Previously, we have shown that chloroquine treatment of mice inhibits T cell responses to MiHC and reduces the development of a miHCdisparate model of GVHD [1]. Interpretation of this data is complicated by the fact that chloroquine can also suppress proinflammatory cytokine secretion from APCs in response to stress or innate immune challenge [44][45][46] and can block sensing of CpG-DNA [47,48]. We thus sought to verify the contribution of MHC II-mediated antigen presentation to the development of miHC-disparate GVHD by directly inhibiting cathepsin S.…”