In vivo evidence for the role of GM-CSF as a mediator in acute pancreatitis-associated lung injury

2002 ◽  
Vol 283 (3) ◽  
pp. L541-L548 ◽  
Author(s):  
Jean Louis Frossard ◽  
Ashok K. Saluja ◽  
Nicolas Mach ◽  
Hong Sik Lee ◽  
Lakshmi Bhagat ◽  
...  
Keyword(s):  
Lung Injury ◽  
Critical Role ◽  
Membrane Thickness ◽  
Myeloperoxidase Activity ◽  
Neutrophil Sequestration ◽  
Gm Csf ◽  
Inflammatory Protein ◽  
Macrophage Colony

Severe pancreatitis is frequently associated with acute lung injury (ALI) and the respiratory distress syndrome. The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mediating the ALI associated with secretagogue-induced experimental pancreatitis was evaluated with GM-CSF knockout mice (GM-CSF −/−). Pancreatitis was induced by hourly (12×) intraperitoneal injection of a supramaximally stimulating dose of the cholecystokinin analog caerulein. The resulting pancreatitis was similar in GM-CSF-sufficient (GM-CSF +/+) control animals and GM-CSF −/− mice. Lung injury, quantitated by measuring lung myeloperoxidase activity (an indicator of neutrophil sequestration), alveolar-capillary permeability, and alveolar membrane thickness was less severe in GM-CSF −/− than in GM-CSF +/+ mice. In GM-CSF +/+ mice, pancreas, lung and serum GM-CSF levels increase during pancreatitis. Lung levels of macrophage inflammatory protein (MIP)-2 are also increased during pancreatitis, but, in this case, the rise is less profound in GM-CSF −/− mice than in GM-CSF +/+ controls. Administration of anti-MIP-2 antibodies was found to reduce the severity of pancreatitis-associated ALI. Our findings indicate that GM-CSF plays a critical role in coupling pancreatitis to ALI and suggest that GM-CSF may act indirectly by regulating the release of other proinflammatory factors including MIP-2.

scholarly journals Eosinophil-specific deletion of IκBα in mice reveals a critical role of NF-κB–induced Bcl-xL for inhibition of apoptosis

Blood ◽  
2015 ◽  
Vol 125 (25) ◽  
pp. 3896-3904 ◽  
Author(s):  
Christian Schwartz ◽  
Ralf Willebrand ◽  
Silke Huber ◽  
Rudolf A. Rupec ◽  
Davina Wu ◽  
...  
Keyword(s):  
Helminth Infection ◽  
Critical Role ◽  
Gm Csf ◽  
Eosinophil Survival ◽  
Key Points ◽  
Specific Deletion ◽  
Specific Inhibitors

Key Points IL-3, IL-5, and GM-CSF promote eosinophil survival by NF-κB–induced upregulation of Bcl-xL, which can be blocked by specific inhibitors. Specific and constitutive deletion of the inhibitor of NF-κB (IκBα) in eosinophils in vivo reduced apoptosis during helminth infection.

The Ig-like domain of human GM-CSF receptor α plays a critical role in cytokine binding and receptor activation

2010 ◽  
Vol 426 (3) ◽  
pp. 307-317 ◽  
Author(s):  
Shamaruh Mirza ◽  
Andrew Walker ◽  
Jinglong Chen ◽  
James M. Murphy ◽  
Ian G. Young
Keyword(s):  
Structural Alignment ◽  
Critical Role ◽  
Receptor Activation ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Subsequent Activation ◽  
Macrophage Colony ◽  
Key Residues ◽  
Stimulating Factor

GM-CSF (granulocyte/macrophage colony-stimulating factor) is an important mediator of inducible haemopoiesis and inflammation, and has a critical role in the function of alveolar macrophages. Its clinical applications include the mobilization of haemopoietic progenitors, and a role as an immune stimulant and vaccine adjuvant in cancer patients. GM-CSF signals via a specific α receptor (GM-CSFRα) and the shared hβc (human common β-subunit). The present study has investigated the role of the Ig-like domain of GM-CSFRα in GM-CSF binding and signalling. Deletion of the Ig-like domain abolished direct GM-CSF binding and decreased growth signalling in the presence of hβc. To locate the specific residues in the Ig-like domain of GM-CSFRα involved in GM-CSF binding, a structural alignment was made with a related receptor, IL-13Rα1 (interleukin-13 receptor α1), whose structure and mode of interaction with its ligand has recently been elucidated. Mutagenesis of candidate residues in the predicted region of interaction identified Val51 and Cys60 as having critical roles in binding to the α receptor, with Arg54 and Leu55 also being important. High-affinity binding in the presence of hβc was strongly affected by mutation of Cys60 and was also reduced by mutation of Val51, Arg54 and Leu55. Of the four key residues, growth signalling was most severely affected by mutation of Cys60. The results indicate a previously unrecognized role for the Ig-like domain, and in particular Cys60, of GM-CSFRα in the binding of GM-CSF and subsequent activation of cellular signalling.

scholarly journals S100A8/A9 modulates inflammatory collateral tissue damage during intraperitoneal origin systemic candidiasis

2020 ◽  
Author(s):  
Madhu Shankar ◽  
Nathalie Uwamahoro ◽  
Sandra Holmberg ◽  
Maria Joanna Niemiec ◽  
Johannes Roth ◽  
...  
Keyword(s):  
Tissue Damage ◽  
Critical Role ◽  
Specific Inhibitor ◽  
Surgical Intensive Care ◽  
Inflammatory Protein ◽  
Systemic Level ◽  
Combating Infection ◽  
Deficient Mice

AbstractPeritonitis is a leading cause of severe sepsis in surgical intensive care units, as over 70% of patients diagnosed with peritonitis develop septic shock. A critical role of the immune system is to return to homeostasis after combating infection. S100A8/A9 (calprotectin) is an antimicrobial, pro-inflammatory protein complex often used as a biomarker for diagnosis of disease activities in many inflammatory disorders. Here we describe the role of S100A8/A9 on inflammatory collateral tissue damage (ICTD).We performed an in vivo Candida albicans disseminated peritonitis mouse model using WT and S100A9-deficient mice and stimulated primary macrophages with recombinant S100A8/A9 in the presence or absence of the compound paquinimod, a specific inhibitor of S100A9. In addition, the effects on ICTD and fungal clearance were investigated. S100A9-deficient mice developed less ICTD than wildtype mice. Restoration of S100A8/A9 in S100A9 knockout mice resulted in increased ICTD and fungal clearance comparable to wildtype levels. Treatment with paquinimod abolished ICTD.The data indicated that S100A8/A9 controls ICTD levels and host antimicrobial modulation at a systemic level during intra-abdominal candidiasis (IAC).

scholarly journals Commitment to the Monocytic Lineage Occurs in the Absence of the Transcription Factor PU.1

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 2849-2858 ◽  
Author(s):  
Gregory W. Henkel ◽  
Scott R. McKercher ◽  
Pieter J.M. Leenen ◽  
Richard A. Maki
Keyword(s):  
Fetal Liver ◽  
Nonspecific Esterase ◽  
Gm Csf ◽  
Cytochemical Analysis ◽  
Latex Beads ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Monocytic Lineage

Mice homozygous for the disruption of the PU.1 (Spi-1) gene do not produce mature macrophages. In determining the role of PU.1 in macrophage differentiation, the present study investigated whether or not there was commitment to the monocytic lineage in the absence of PU.1. Early PU.1−/− myeloid colonies were generated from neonate liver under conditions that promote primarily macrophage and granulocyte/macrophage colonies. These PU.1−/− colonies were found to contain cells with monocytic characteristics as determined by nonspecific esterase stain and the use of monoclonal antibodies that recognize early monocyte precursors, including Moma-2, ER-MP12, ER-MP20, and ER-MP58. In addition, early myeloid cells could be grown from PU.1−/− fetal liver cultures in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). Similar to the PU.1 null colonies, the GM-CSF–dependent cells also possessed early monocytic characteristics, including the ability to phagocytize latex beads. The ability of PU.1−/− progenitors to commit to the monocytic lineage was also verified in vivo by flow cytometry and cytochemical analysis of primary neonate liver cells. The combined data shows that PU.1 is absolutely required for macrophage development after commitment to this lineage.

scholarly journals GM-CSF–dependent, CD103+ dermal dendritic cells play a critical role in Th effector cell differentiation after subcutaneous immunization

2010 ◽  
Vol 207 (5) ◽  
pp. 953-961 ◽  
Author(s):  
Irah L. King ◽  
Mark A. Kroenke ◽  
Benjamin M. Segal
Keyword(s):  
Dendritic Cells ◽  
Cell Differentiation ◽  
Critical Role ◽  
Th1 Cell ◽  
Gm Csf ◽  
Inflammatory Conditions ◽  
Th Cell ◽  
Macrophage Colony ◽  
Subcutaneous Immunization

Dendritic cells (DCs) play an important role in CD4+ T helper (Th) cell differentiation and in the initiation of both protective and pathogenic immunity. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a DC growth factor critical for the induction of experimental autoimmune encephalomyelitis (EAE) and other autoimmune diseases, yet its mechanism of action in vivo is not fully defined. We show that GM-CSF is directly required for the accumulation of radiosensitive dermal-derived langerin+CD103+ DCs in the skin and peripheral lymph nodes under steady-state and inflammatory conditions. Langerin+CD103+ DCs stimulated naive myelin-reactive T cells to proliferate and produce IFN-γ and IL-17. They were superior to other DC subsets in inducing expression of T-bet and promoting Th1 cell differentiation. Ablation of this subset in vivo conferred resistance to EAE. The current report reveals a previously unidentified role for GM-CSF in DC ontogeny and identifies langerin+CD103+ DCs as an important subset in CD4+ T cell–mediated autoimmune disease.

scholarly journals Critical Role of the Interleukin-17/Interleukin-17 Receptor Axis in Regulating Host Susceptibility to Respiratory Infection with Chlamydia Species

2009 ◽  
Vol 77 (11) ◽  
pp. 5059-5070 ◽  
Author(s):  
Xiaohui Zhou ◽  
Qiangwei Chen ◽  
Jessica Moore ◽  
Jay K. Kolls ◽  
Scott Halperin ◽  
...  
Keyword(s):  
Respiratory Infection ◽  
Critical Role ◽  
Lung Parenchyma ◽  
Host Susceptibility ◽  
Interleukin 17 ◽  
Chlamydia Muridarum ◽  
Inflammatory Protein ◽  
First Time

ABSTRACT The specific contribution of interleukin-17/interleukin-17 receptor (IL-17/IL-17R)-mediated responses in regulating host susceptibility against obligatory intracellular Chlamydia infection was investigated in C57BL/6 and C3H/HeN mice during Chlamydia muridarum respiratory infection. We demonstrated that Chlamydia stimulated IL-17/IL-17R-associated responses in both Chlamydia-resistant C57BL/6 and Chlamydia-susceptible C3H/HeN mice. However, C3H/HeN mice developed a significantly greater IL-17/IL-17R-associated response than C57BL/6 mice did. This was reflected by an increase in IL-17 mRNA expression, a higher recall IL-17 production from splenocytes upon antigen restimulation, and higher production of Th17-related cytokines (IL-23 and IL-6) and chemokines (chemokine [C-X-C motif] ligand 2 [CXCL1]/keratinocyte-derived chemokine [KC] and CXCL2/macrophage inflammatory protein 1 [MIP2]) in C3H/HeN mice than in C57BL/6 mice. Furthermore, C3H/HeN mice displayed a massive accumulation of activated and preactivated neutrophils in the airway and lung parenchyma compared to their C57BL/6 counterparts. We further demonstrated that the skewed IL-17/Th17 profile in C3H/HeN mice was predisposed by a higher basal level of IL-17 receptor C (IL-17RC) expression and then further amplified by a higher inducible IL-17RA expression in lungs. Most importantly, in vivo delivery of IL-17RA antagonist that resulted in a 50% reduction in the neutrophilic infiltration in lungs was able to reverse the susceptible phenotype of C3H/HeN mice to respiratory Chlamydia infection. Thus, our data for the first time have demonstrated a critical role for the IL-17/IL-17R axis in regulating host susceptibility to Chlamydia infection in mice.

scholarly journals Commitment to the Monocytic Lineage Occurs in the Absence of the Transcription Factor PU.1

Blood ◽  
1999 ◽  
Vol 93 (9) ◽  
pp. 2849-2858 ◽  
Author(s):  
Gregory W. Henkel ◽  
Scott R. McKercher ◽  
Pieter J.M. Leenen ◽  
Richard A. Maki
Keyword(s):  
Fetal Liver ◽  
Nonspecific Esterase ◽  
Gm Csf ◽  
Cytochemical Analysis ◽  
Latex Beads ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Monocytic Lineage

Abstract Mice homozygous for the disruption of the PU.1 (Spi-1) gene do not produce mature macrophages. In determining the role of PU.1 in macrophage differentiation, the present study investigated whether or not there was commitment to the monocytic lineage in the absence of PU.1. Early PU.1−/− myeloid colonies were generated from neonate liver under conditions that promote primarily macrophage and granulocyte/macrophage colonies. These PU.1−/− colonies were found to contain cells with monocytic characteristics as determined by nonspecific esterase stain and the use of monoclonal antibodies that recognize early monocyte precursors, including Moma-2, ER-MP12, ER-MP20, and ER-MP58. In addition, early myeloid cells could be grown from PU.1−/− fetal liver cultures in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). Similar to the PU.1 null colonies, the GM-CSF–dependent cells also possessed early monocytic characteristics, including the ability to phagocytize latex beads. The ability of PU.1−/− progenitors to commit to the monocytic lineage was also verified in vivo by flow cytometry and cytochemical analysis of primary neonate liver cells. The combined data shows that PU.1 is absolutely required for macrophage development after commitment to this lineage.

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