Diversity of Interferon γ and Granulocyte-Macrophage Colony-Stimulating Factor in Restoring Immune Dysfunction of Dendritic Cells and Macrophages During Polymicrobial Sepsis

Abstract

The development of immunosuppression during polymicrobial sepsis is associated with the failure of dendritic cells (DC) to promote the polarization of T helper (Th) cells toward a protective Th1 type. The aim of the study was to test potential immunomodulatory approaches to restore the capacity of splenic DC to secrete interleukin (IL) 12 that represents the key cytokine in Th1 cell polarization. Murine polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Splenic DC were isolated at different time points after CLP or sham operation, and stimulated with bacterial components in the presence or absence of neutralizing anti-IL-10 antibodies, murine interferon (IFN) γ, and/or granulocyte macrophage colony-stimulating factor (GM-CSF). DC from septic mice showed an impaired capacity to release the pro-inflammatory and Th1-promoting cytokines tumor necrosis factor α, IFN-γ, and IL-12 in response to bacterial stimuli, but secreted IL-10. Endogenous IL-10 was not responsible for the impaired IL-12 secretion. Up to 6 h after CLP, the combined treatment of DC from septic mice with IFN-γ and GM-CSF increased the secretion of IL-12. Later, DC from septic mice responded to IFN-γ and GM-CSF with increased expression of the co-stimulatory molecule CD86, while IL-12 secretion was no more enhanced. In contrast, splenic macrophages from septic mice during late sepsis responded to GM-CSF with increased cytokine release. Thus, therapy of sepsis with IFN-γ/GM-CSF might be sufficient to restore the activity of macrophages, but fails to restore DC function adequate for the development of a protective Th1-like immune response.

Effect of Cholecalciferol Supplementation on Vitamin D Status and Cathelicidin Levels in Sepsis

“…It is normally not detectable in the plasma of healthy humans, but levels can be elevated in patients with sepsis [66]. Recent evidence suggests that IFN-γ may play an important role in the reversal of sepsis-induced immunoparalysis [67,68]. In contrast, expression of IL-10 is largely associated with anti-inflammatory functions, such as suppression of pro-inflammatory mediators (e.g.…”

Sepsis: Multiple Abnormalities, Heterogeneous Responses, and Evolving Understanding

“…However, studies indicate that many of these functions are compromised during sepsis. Monocytes isolated from animal models and patients with sepsis release lower amounts of proinflammatory cytokines when stimulated with Toll-like receptor ligands, suggesting that their capacity to sense and respond to new infections is impaired (6,112,220,257). In septic humans, the expression of HLA-DR is markedly decreased (174,257); however, sur- vivors demonstrate a significant recovery of HLA-DR expression compared with nonsurvivors (247,248,439).…”

Mechanisms of sepsis‐induced immunosuppression and immunological modification therapies for sepsis

“…Most patients with sepsis are severely immunosuppressed. Treatment with GM‐CSF was predicted to reverse the dysfunction of dendritic cells and monocytes/macrophages 41. G‐CSF was used to increase the number of polymorphonuclear leukocytes in an effort to enhance pathogen clearance.…”