GM-CSF Restores Innate, But Not Adaptive, Immune Responses in Glucocorticoid-Immunosuppressed Human Blood In Vitro

Xu, Jian; Lucas, Rudolf; Schuchmann, Marcus; Kühnle, Simone; Meergans, Thomas; Barreiros, Ana Paula; Lohse, Ansgar W.; Otto, Gerd; Wendel, Albrecht

doi:10.4049/jimmunol.171.2.938

Cited by 24 publications

(18 citation statements)

References 67 publications

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“…These findings suggested that such differentiated M could evoke abnormal inflammation because they produced large amounts of TNF-␣ and MMP-9, even, without TNF-priming. However, GM-CSF is known to induce M, termed proinflammatory type 1 M (51), which have important roles in defense against infection (52), but a limited role in adaptive immunity (53). These data are consistent with our results.…”

Section: Discussionsupporting

confidence: 91%

TNF-α Drives Human CD14+ Monocytes to Differentiate into CD70+ Dendritic Cells Evoking Th1 and Th17 Responses

Iwamoto¹,

Iwai²,

Tsujiyama³

et al. 2007

The Journal of Immunology

144

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Many mechanisms involving TNF-α, Th1 responses, and Th17 responses are implicated in chronic inflammatory autoimmune disease. Recently, the clinical impact of anti-TNF therapy on disease progression has resulted in re-evaluation of the central role of this cytokine and engendered novel concept of TNF-dependent immunity. However, the overall relationship of TNF-α to pathogenesis is unclear. Here, we demonstrate a TNF-dependent differentiation pathway of dendritic cells (DC) evoking Th1 and Th17 responses. CD14+ monocytes cultured in the presence of TNF-α and GM-CSF converted to CD14+ CD1alow adherent cells with little capacity to stimulate T cells. On stimulation by LPS, however, they produced high levels of TNF-α, matrix metalloproteinase (MMP)-9, and IL-23 and differentiated either into mature DC or activated macrophages (Mφ). The mature DC (CD83+ CD70+ HLA-DR high CD14low) expressed high levels of mRNA for IL-6, IL-15, and IL-23, induced naive CD4 T cells to produce IFN-γ and TNF-α, and stimulated resting CD4 T cells to secret IL-17. Intriguingly, TNF-α added to the monocyte culture medium determined the magnitude of LPS-induced maturation and the functions of the derived DC. In contrast, the Mφ (CD14highCD70+CD83−HLA-DR−) produced large amounts of MMP-9 and TNF-α without exogenous TNF stimulation. These results suggest that the TNF priming of monocytes controls Th1 and Th17 responses induced by mature DC, but not inflammation induced by activated Mφ. Therefore, additional stimulation of monocytes with TNF-α may facilitate TNF-dependent adaptive immunity together with GM-CSF-stimulated Mφ-mediated innate immunity.

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Section: Discussionsupporting

confidence: 91%

TNF-α Drives Human CD14+ Monocytes to Differentiate into CD70+ Dendritic Cells Evoking Th1 and Th17 Responses

Iwamoto¹,

Iwai²,

Tsujiyama³

et al. 2007

The Journal of Immunology

144

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“…The contrasting effects of GM-CSF and DEX may also occur via the amount of expression of dectin-1, the major macrophage receptor for b-glucans [23]. Support for our model of GM-CSF-mediated resistance to DEX-induced inhibition of conidia-stimulated NF-kB activation was recently reported in a study in which LPS was used instead of conidia [24]. In that study, GM-CSF restored expression of mRNA for TNF-a that was suppressed by DEX in human peripheral blood mononuclear cells in response to LPS.…”

Section: Discussionsupporting

confidence: 53%

“…We postulated that this was due to low levels of receptors for GM-CSF in lymphocytes. In support of this concept, Xu et al showed that GM-CSF neither caused graft rejection in DEXtreated mouse graft recipients nor reversed the DEX-suppressed proliferative response of lymphocytes [24]. However, GM-CSF reversed DEX immunosuppression in a model of lethal Salmonella typhimurium infection in which GM-CSF significantly increased survival [24].…”

Section: Discussionmentioning

confidence: 81%

Inhibitor κB and Nuclear Factor κB in Granulocyte‐Macrophage Colony‐Stimulating Factor Antagonism of Dexamethasone Suppression of the Macrophage Response toAspergillus fumigatusConidia

et al. 2006

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Background. The dexamethasone (DEX) immunosuppressive effect on macrophage killing activity and cytokine production in response to Aspergillus fumigatus conidia is antagonized by granulocyte-macrophage colony-stimulating factor (GM-CSF). The molecular mechanism is unknown. We postulated that this antagonism is mediated by inhibitor kB (IkB) induction by DEX and is opposed by acceleration of IkB degradation by GM-CSF with or without conidia stimulation, with corresponding effects on translocation and activation of nuclear factor kB (NF-kB).Methods. We studied 2 types of cells, resident peritoneal macrophages from CD-1 mice and the murine macrophage RAW264.7 cell line. Cells were unstimulated or stimulated with conidia and simultaneously treated with DEX, GM-CSF, or DEX plus GM-CSF, for 2-4 hours. IkB degradation and NF-kB activation were assessed by Western blot.Results. Macrophages stimulated with conidia alone increased NF-kB translocation. DEX increased IkB levels in cytoplasm and blocked translocation of NF-kB to the nucleus in unstimulated and conidia-stimulated macrophages. Conversely, GM-CSF decreased IkB levels. GM-CSF reversed the effect of DEX on IkB levels. NF-kB levels were minimal in DEX-treated macrophage nuclear extracts, compared with those from GM-CSF-treated and GM-CSF plus DEX-treated macrophages.Conclusion. GM-CSF can reverse the DEX immunosuppressive effect by enhancing IkB degradation and promoting NF-kB translocation. This would allow macrophage production of proinflammatory cytokines, facilitating resistance to aspergillosis.

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“…Short-term treatment with GM-CSF has been shown to counteract impaired innate immune function due to a variety of insults. Ex vivo exposure to GM-CSF has restored function in monocytes harvested from humans with septic shock (36) or from immunosuppressed liver transplant recipients (37). In a rat model of hemorrhagic shock, GM-CSF treatment in vivo has corrected tissue macrophage dysfunction (17).…”

Section: Discussionmentioning

confidence: 99%

GM-CSF and the impaired pulmonary innate immune response following hyperoxic stress

Baleeiro¹,

Christensen²,

Morris³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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We have previously demonstrated that mice exposed to sublethal hyperoxia (an atmosphere of Ͼ95% oxygen for 4 days, followed by return to room air) have significantly impaired pulmonary innate immune response. Alveolar macrophages (AM) from hyperoxia-exposed mice exhibit significantly diminished antimicrobial activity and markedly reduced production of inflammatory cytokines in response to stimulation with LPS compared with AM from control mice in normoxia. As a consequence of these defects, mice exposed to sublethal hyperoxia are more susceptible to lethal pneumonia with Klebsiella pneumoniae than control mice. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a growth factor produced by normal pulmonary alveolar epithelial cells that is critically involved in maintenance of normal AM function. We now report that sublethal hyperoxia in vivo leads to greatly reduced alveolar epithelial cell GM-CSF expression. Systemic treatment of mice with recombinant murine GM-CSF during hyperoxia exposure preserved AM function, as indicated by cell surface Toll-like receptor 4 expression and by inflammatory cytokine secretion following stimulation with LPS ex vivo. Treatment of hyperoxic mice with GM-CSF significantly reduced lung bacterial burden following intratracheal inoculation with K. pneumoniae, returning lung bacterial colony-forming units to the level of normoxic controls. These data point to a critical role for continuous GM-CSF activity in the lung in maintenance of normal AM function and demonstrate that lung injury due to hyperoxic stress results in significant impairment in pulmonary innate immunity through suppression of alveolar epithelial cell GM-CSF expression.

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GM-CSF Restores Innate, But Not Adaptive, Immune Responses in Glucocorticoid-Immunosuppressed Human Blood In Vitro

Cited by 24 publications

References 67 publications

TNF-α Drives Human CD14+ Monocytes to Differentiate into CD70+ Dendritic Cells Evoking Th1 and Th17 Responses

TNF-α Drives Human CD14+ Monocytes to Differentiate into CD70+ Dendritic Cells Evoking Th1 and Th17 Responses

Inhibitor κB and Nuclear Factor κB in Granulocyte‐Macrophage Colony‐Stimulating Factor Antagonism of Dexamethasone Suppression of the Macrophage Response toAspergillus fumigatusConidia

GM-CSF and the impaired pulmonary innate immune response following hyperoxic stress

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