scholarly journals Early Colorectal Responses to HIV-1 and Modulation by Antiretroviral Drugs

Vaccines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 231
Author(s):  
Carolina Herrera ◽  
Mike D. McRaven ◽  
Ken G. Laing ◽  
Jayne Dennis ◽  
Thomas J. Hope ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Ex Vivo ◽  
Interferon Γ ◽  
Antiretroviral Drugs ◽  
Limited Information ◽  
Acute Hiv Infection ◽  
Colorectal Tissue ◽  
Gm Csf ◽  
Macrophage Colony ◽  
Hiv 1

Innate responses during acute HIV infection correlate with disease progression and pathogenesis. However, limited information is available about the events occurring during the first hours of infection in the mucosal sites of transmission. With an ex vivo HIV-1 challenge model of human colorectal tissue we assessed the mucosal responses induced by R5- and X4-tropic HIV-1 isolates in the first 24 h of exposure. Microscopy studies demonstrated virus penetration of up to 39 μm into the lamina propia within 6 h of inoculation. A rapid, 6 h post-challenge, increase in the level of secretion of inflammatory cytokines, chemokines, interferon- γ (IFN-γ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) was observed following exposure to R5- or X4-tropic isolates. This profile persisted at the later time point measured of 24 h. However, exposure to the X4-tropic isolate tested induced greater changes at the proteomic and transcriptomic levels than the R5-tropic. The X4-isolate induced greater levels of CCR5 ligands (RANTES, MIP-1α and MIP-1β) secretion than R5-HIV-1. Potential drugs candidates for colorectal microbicides, including entry, fusion or reverse transcriptase inhibitors demonstrated differential capacity to modulate these responses. Our findings indicate that in colorectal tissue, inflammatory responses and a Th1 cytokine profile are induced in the first 24 h following viral exposure.

GM-CSF, via PU.1, regulates alveolar macrophage FcγR-mediated phagocytosis and the IL-18/IFN-γ–mediated molecular connection between innate and adaptive immunity in the lung

Blood ◽  
2002 ◽  
Vol 100 (12) ◽  
pp. 4193-4200 ◽  
Author(s):  
Pierre-Yves Berclaz ◽  
Yoko Shibata ◽  
Jeffrey A. Whitsett ◽  
Bruce C. Trapnell
Keyword(s):  
Ex Vivo ◽  
Lung Infection ◽  
Surfactant Protein ◽  
Interferon Γ ◽  
Adenoviral Infection ◽  
Gm Csf ◽  
Ifn Γ ◽  
Macrophage Colony

Severely impaired pulmonary microbial clearance was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)–deficient mice. To determine mechanisms by which GM-CSF mediates lung host defense, FcγR-mediated phagocytosis (opsonophagocytosis) by alveolar macrophages (AMs) was assessed in GM-CSF–sufficient (GM+/+) and –deficient (GM−/−) mice and in GM−/− mice expressing GM-CSF only in the lungs from a surfactant protein C (SPC) promoter (SPC-GM+/+/GM−/−). Opsonophagocytosis by GM−/− AMs was severely impaired and was restored by pulmonary GM-CSF expression in vivo or by PU.1 expression in vitro. Defective opsonophagocytosis by GM−/− AMs was associated with decreased FcγR expression. Because interferon-γ (IFN-γ) augments macrophage FcγR levels, the role of GM-CSF/PU.1 in the regulation of AM FcγR expression by IFN-γ was assessed during adenoviral lung infection. Adenoviral infection stimulated IFN-γ production and augmented FcγR levels on AMs in GM-CSF–expressing but not GM−/− mice. However, IFN-γ exposure ex vivo stimulated FcγR expression on GM−/− AMs. Because interleukin-18 (IL-18) and IL-12 stimulate IFN-γ production during adenoviral infection, their role in GM-CSF/PU.1 regulation of IFN-γ–augmented FcγR expression on AMs was assessed. Adenoviral infection stimulated IL-18 and IL-12 production in GM-CSF–expressing mice, but both were markedly reduced or absent in GM−/−mice. IL-18 expression by GM−/− AMs was severely impaired and was restored by pulmonary GM-CSF expression in vivo or by PU.1 expression in vitro. Pulmonary administration of IL-18 in GM−/− mice stimulated IFN-γ production and restored FcγR expression on AMs. These results show that GM-CSF, via PU.1, regulates constitutive AM FcγR expression and opsonophagocytosis and is required for the IFN-γ–dependent regulation of AM FcγR expression, enabling AMs to release IL-18/IL-12 during lung infection.

scholarly journals CSF-induced and HIV-1–mediated Distinct Regulation of Hck and C/EBPβ Represent a Heterogeneous Susceptibility of Monocyte-derived Macrophages to M-tropic HIV-1 Infection

2003 ◽  
Vol 198 (3) ◽  
pp. 443-453 ◽  
Author(s):  
Iwao Komuro ◽  
Yasuko Yokota ◽  
Sachiko Yasuda ◽  
Aikichi Iwamoto ◽  
Kiyoko S. Kagawa
Keyword(s):  
Viral Replication ◽  
Virus Production ◽  
High Rate ◽  
Moderate Amount ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
High Level ◽  
Stimulating Factor ◽  
Hiv 1

Granulocyte/macrophage colony-stimulating factor (GM-CSF)–induced monocyte-derived macrophages (GM-MΦ) are permissive to M-tropic HIV-1 entry, but inhibit viral replication at posttranscriptional and translational levels, whereas M-CSF-induced macrophages (M-MΦ) produce a large amount of HIV-1. M-MΦ express a high level of Hck and a large isoform of C/EBPβ, and HIV-1 infection increases the expression of Hck but not of C/EBPβ. GM-MΦ express a high level of C/EBPβ and a low level of Hck, and HIV-1 infection drastically increases the expression of a short isoform of C/EBPβ but decreases that of Hck. Treatment of M-MΦ with antisense oligonucleotide for Hck (AS-Hck) not only suppresses the expression of Hck, but also stimulates the induction of the short isoform of C/EBPβ and inhibits the viral replication. Treatment of GM-MΦ with a moderate amount of AS-C/EBPβ not only inhibits the expression of the small isoform of C/EBPβ preferentially, but also stimulates the induction of Hck and stimulates the virus production at a high rate. These results suggest that CSF-induced and HIV-1–mediated distinct regulation of Hck and small isoform of C/EBPβ represent the heterogeneous susceptibility of tissue MΦ to HIV-1 infection, and the regulation of Hck and C/EBPβ are closely related and these two molecules affect one another.

Granulocyte-Macrophage Colony-Stimulating Factor Upregulates Reduced 5-Lipoxygenase Metabolism in Peripheral Blood Monocytes and Neutrophils in Acquired Immunodeficiency Syndrome

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3897-3905 ◽  
Author(s):  
Michael J. Coffey ◽  
Susan M. Phare ◽  
Sandro Cinti ◽  
Marc Peters-Golden ◽  
Powel H. Kazanjian
Keyword(s):  
Acquired Immunodeficiency Syndrome ◽  
Peripheral Blood ◽  
Ex Vivo ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Acquired Immunodeficiency ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Immunodeficiency Syndrome ◽  
Stimulating Factor

Abstract Leukotrienes (LT) are mediators derived from the 5-lipoxygenase (5-LO) pathway, which play a role in host defense, and are synthesized by both monocytes (peripheral blood monocyte [PBM]) and neutrophils (PMN). Because 5-LO metabolism is reduced in alveolar macrophages and PMN from acquired immunodeficiency syndrome (AIDS) subjects, we investigated the synthesis of LT by PBM and PMN from these subjects. There was a reduction (74.2% ± 8.8% of control) in LT synthesis in PBM from human immunodeficiency virus (HIV)-infected compared with normal subjects. Expression of 5-LO (51.2% ± 8.8% of control), and 5-LO activating protein (FLAP) (48.5% ± 8.0% of control) was reduced in parallel. We hypothesized that this reduction in LT synthetic capacity in PBM and PMN was due to reduced cytokine production by CD4 T cells, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). We treated 10 AIDS subjects with GM-CSF for 5 days. PBM 5-LO metabolism ex vivo was selectively increased after GM-CSF therapy and was associated with increased 5-LO and FLAP expression. PMN leukotriene B4(LTB4) synthesis was also augmented and associated with increased 5-LO, FLAP, and cytosolic phospholipase A2 expression. In conclusion, as previously demonstrated for PMN, PBM from AIDS subjects also demonstrate reduced 5-LO metabolism. GM-CSF therapy reversed this defect in both PBM and PMN. In view of the role of LT in antimicrobial function, cytokine administration in AIDS may play a role as adjunct therapy for infections.

scholarly journals Tofacitinib Reprograms Human Monocytes of IBD Patients and Healthy Controls Toward a More Regulatory Phenotype

2019 ◽  
Vol 26 (3) ◽  
pp. 391-406 ◽  
Author(s):  
Friederike Cordes ◽  
Eva Lenker ◽  
Lea J Spille ◽  
Toni Weinhage ◽  
Dominik Bettenworth ◽  
...  
Keyword(s):  
Cellular Response ◽  
Inflammatory Responses ◽  
Healthy Controls ◽  
Regulatory Pathways ◽  
Gm Csf ◽  
Bowel Diseases ◽  
Activated Monocytes ◽  
Macrophage Colony ◽  
The Impact ◽  
Regulatory Phenotype

Abstract Background The inhibition of Janus kinases (JAKs) and subsequent signal transducers and activators of transcription (STATs) by tofacitinib represents a new therapeutic strategy in inflammatory bowel diseases (IBD) as clinical trials have led to approval of tofacitinib for ulcerative colitis (UC) and hint at a possible efficacy for Crohn`s disease (CD). However, the impact of tofacitinib on cellular response of monocytes, which are key players in inflammatory responses, has not been investigated so far. We aimed to analyze JAK/STAT-inhibition by tofacitinib in monocytes of IBD patients and healthy controls. Methods Primary monocytes of IBD patients with active disease and healthy controls (n = 18) were analyzed for cytokine expression and phenotype after granulocyte macrophage colony-stimulating factor (GM-CSF)/interferon (IFN)γ-stimulation and tofacitinib pretreatment (1–1000 nM) and capacity to induce Foxp3+-regulatory T cells (Tregs) in cocultures. In total, 20 UC patients and 21 CD patients were included. Additionally, dose-dependent inhibition of JAK/STAT-phosphorylation was analyzed in controls. Results Pro-inflammatory costimulation with GM-CSF/IFNγ resulted in significant tumor necrosis factor (TNFα) and interleukin (IL)-6 increase, whereas IL-10 expression decreased in monocytes. Tofacitinib modulated the responses of activated monocytes toward a regulatory phenotype through reduced TNFα and IL-6 secretion and enhanced Treg induction in cocultures. However, in monocytes from active IBD patients, higher tofacitinib dosages were needed for blockade of pro-inflammatory cytokines. Tofacitinib induced stronger regulatory phenotypes in monocytes of UC patients, including more effective inhibition of pro-inflammatory pathways and better restoration of anti-inflammatory mechanisms as compared with CD-derived monocytes. Conclusion Tofacitinib dose-dependently reprograms monocytes toward a more regulatory cell type. This beneficial effect possibly results from selective JAK/STAT-blockade by adequate tofacitinib dosage with inhibition of pro-inflammatory responses and permission of a balance-shift toward regulatory pathways.

scholarly journals Comparison of the Inflammatory Responses of Human Meningeal Cells following Challenge with Neisseria lactamica and with Neisseria meningitidis

2006 ◽  
Vol 74 (11) ◽  
pp. 6467-6478 ◽  
Author(s):  
Mark I. Fowler ◽  
Kiave Y. Ho Wang Yin ◽  
Holly E. Humphries ◽  
John E. Heckels ◽  
Myron Christodoulides
Keyword(s):  
Neisseria Meningitidis ◽  
Inflammatory Responses ◽  
Host Cells ◽  
Pathogenic Potential ◽  
Monocyte Chemoattractant Protein 1 ◽  
Gm Csf ◽  
Neisseria Lactamica ◽  
Meningeal Cells ◽  
Macrophage Colony

ABSTRACT The rationale for the present study was to determine how different species of bacteria interact with cells of the human meninges in order to gain information that would have broad relevance to understanding aspects of the innate immune response in the brain. Neisseria lactamica is an occasional cause of meningitis in humans, and in this study we investigated the in vitro interactions between N. lactamica and cells derived from the leptomeninges in comparison with the closely related organism Neisseria meningitidis, a major cause of meningitis worldwide. N. lactamica adhered specifically to meningioma cells, but the levels of adherence were generally lower than those with N. meningitidis. Meningioma cells challenged with N. lactamica and N. meningitidis secreted significant amounts of the proinflammatory cytokine interleukin-6 (IL-6), the C-X-C chemokine IL-8, and the C-C chemokines monocyte chemoattractant protein 1 (MCP-1) and RANTES, but it secreted very low levels of the cytokine growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF). Thus, meningeal cells are involved in the innate host response to Neisseria species that are capable of entering the cerebrospinal fluid. The levels of IL-8 and MCP-1 secretion induced by both bacteria were essentially similar. By contrast, N. lactamica induced significantly lower levels of IL-6 than N. meningitidis. Challenge with the highest concentration of N. lactamica (108 CFU) induced a small but significant down-regulation of RANTES secretion, which was not observed with lower concentrations of bacteria. N. meningitidis (106 to 108 CFU) also down-regulated RANTES secretion, but this effect was significantly greater than that observed with N. lactamica. Although both bacteria were unable to invade meningeal cells directly, host cells remained viable on prolonged challenge with N. lactamica, whereas N. meningitidis induced death; the mechanism was overwhelming necrosis with no significant apoptosis. It is likely that differential expression of modulins between N. lactamica and N. meningitidis contributes to these observed differences in pathogenic potential.

Interferon-γ switches monocyte differentiation from dendritic cells to macrophages

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 143-150 ◽  
Author(s):  
Yves Delneste ◽  
Peggy Charbonnier ◽  
Nathalie Herbault ◽  
Giovanni Magistrelli ◽  
Gersende Caron ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Interferon Γ ◽  
Transcriptional Level ◽  
Colony Stimulating Factor ◽  
Monocyte Differentiation ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Ifn Γ ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Human monocytes differentiate into dendritic cells (DCs) or macrophages according to the nature of environmental signals. Monocytes stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) plus interleukin 4 (IL-4) yield DCs. We tested here whether interferon-γ (IFN-γ), a potent activator of macrophages, may modulate monocyte differentiation. Addition of IFN-γ to IL-4 plus GM-CSF–stimulated monocytes switches their differentiation from DCs to CD14−CD64+ macrophages. IFN-γ increases macrophage colony-stimulating factor (M-CSF) and IL-6 production by IL-4 plus GM-CSF–stimulated monocytes by acting at the transcriptional level and acts together with IL-4 to up-regulate M-CSF but not IL-6 production. IFN-γ also increases M-CSF receptor internalization. Results from neutralizing experiments show that both M-CSF and IL-6 are involved in the ability of IFN-γ to skew monocyte differentiation from DCs to macrophages. Finally, this effect of IFN-γ is limited to early stages of differentiation. When added to immature DCs, IFN-γ up-regulates IL-6 but not M-CSF production and does not convert them to macrophages, even in the presence of exogenous M-CSF. In conclusion, IFN-γ shifts monocyte differentiation to macrophages rather than DCs through autocrine M-CSF and IL-6 production. These data show that IFN-γ controls the differentiation of antigen-presenting cells and thereby reveals a new mechanism by which IFN-γ orchestrates the outcome of specific immune responses.

scholarly journals Deficiencies of GM-CSF and Interferon γ Link Inflammation and Cancer

2003 ◽  
Vol 197 (9) ◽  
pp. 1213-1219 ◽  
Author(s):  
Thomas Enzler ◽  
Silke Gillessen ◽  
John P. Manis ◽  
David Ferguson ◽  
James Fleming ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Tumor Development ◽  
Interferon Γ ◽  
Systemic Lupus Erythematosis ◽  
Critical Determinant ◽  
Gm Csf ◽  
Infection And Inflammation ◽  
Macrophage Colony ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Chronic inflammation contributes to carcinogenesis, but the underlying mechanisms are poorly understood. We report that aged granulocyte-macrophage colony stimulating factor (GM-CSF)-deficient mice develop a systemic lupus erythematosis (SLE)-like disorder associated with the impaired phagocytosis of apoptotic cells. Concurrent deficiency of interferon (IFN)-γ attenuates the SLE, but promotes the formation of diverse hematologic and solid neoplasms within a background of persistent infection and inflammation. Whereas activated B cells show a resistance to fas-induced apoptosis, antimicrobial therapy prevents lymphomagenesis and solid tumor development. These findings demonstrate that the interplay of infectious agents with cytokine-mediated regulation of immune homeostasis is a critical determinant of cancer susceptibility.

scholarly journals Antifungal Activities of Posaconazole and Granulocyte-Macrophage Colony-Stimulating Factor Ex Vivo and in Mice with Disseminated Infection Due to Scedosporium prolificans

2004 ◽  
Vol 48 (10) ◽  
pp. 3801-3805 ◽  
Author(s):  
M. Simitsopoulou ◽  
C. Gil-Lamaignere ◽  
N. Avramidis ◽  
A. Maloukou ◽  
S. Lekkas ◽  
...  
Keyword(s):  
Ex Vivo ◽  
High Rate ◽  
Invasive Infection ◽  
Colony Stimulating Factor ◽  
Disseminated Infection ◽  
Gm Csf ◽  
Scedosporium Prolificans ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

ABSTRACT Invasive infection due to Scedosporium prolificans is characterized by drug resistance and a high rate of mortality. The effects of posaconazole (POS), an investigational antifungal triazole, murine granulocyte-macrophage colony-stimulating factor (GM-CSF), and their combination against S. prolificans were evaluated ex vivo and in a newly developed murine model of disseminated infection due to this organism. When POS was combined with polymorphonuclear leukocytes from untreated or GM-CSF-treated mice (P < 0.01) ex vivo, it had increased activity in terms of the percentage of hyphal damage. Immunocompetent BALB/c mice were infected with 4 × 104 conidia of S. prolificans via the lateral tail vein. At 24 h postinfection the mice were treated with GM-CSF (5 μg/kg of body weight/day subcutaneously), POS (50 mg/kg/day by gavage), both agents, or saline only. Half of the brain, lung, liver, and kidney from each animal were cultured; and the other half of each organ was processed for histopathology. The mean survival times were 7.0 ± 0.3 days for the controls, 7.4 ± 0.4 days for POS-treated mice, 8.0 ± 0.3 days for GM-CSF-treated mice (P = 0.08 compared with the results for the controls), and 7.3 ± 0.3 days for POS-GM-CSF-treated mice. Fungal burdens (determined as the numbers of CFU per gram of tissue) were found in descending orders of magnitude in the kidneys, brains, livers, and lungs. The burdens were significantly reduced in the brains of GM-CSF-treated mice (P < 0.05) and the livers of POS-treated mice (P < 0.05). The numbers of lesions in the organs closely corresponded to the fungal burdens. GM-CSF tended to prolong survival (P = 0.08 compared with the results for the controls). While the combination of POS and GM-CSF showed enhanced activity ex vivo, it did not increase the activities of the two agents against this highly refractory filamentous fungus in mice.

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