Time course of granulocyte–macrophage colony-stimulating factor and IL-8 in severe sepsis: are the initial low levels of IL-8 a consequence of immunodepression?

Bone marrow stromal cells influence hematopoiesis through cell-cell interaction and release of hematopoietic growth factors. Macrophage colony-stimulating factor (M-CSF) is constitutively produced by several murine and human stromal cell lines and is induced by inflammatory mediators such as interleukin-1 alpha or tumor necrosis factor-alpha (TNF-alpha) in a variety of mesenchymal cells. Other potentially important regulatory molecules such as platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), released by activated monocytes in response to inflammation, stimulate the growth of human stromal cells. However, the effect of these peptide mitogens on M-CSF expression in stromal cells has not been explored. In this study, we used TC-1 murine bone marrow-derived stromal cells that constitutively secrete M-CSF to determine the effect of PDGF and bFGF on cell proliferation and M-CSF gene expression. PDGF and bFGF, but not TNF- alpha, were potent mitogens for the TC-1 cells. Similar to mouse L cells, TC-1 murine stromal cells constitutively expressed two major mRNA transcripts of 4.4 and 2.2 kb that hybridized to a murine M-CSF cDNA. PDGF, bFGF, and TNF-alpha markedly stimulated the steady-state expression of M-CSF mRNA with different time-course kinetics. The increased expression of M-CSF mRNA was associated with enhanced secretion of M-CSF as determined by radioimmunoassay. These findings suggest that PDGF, bFGF, and TNF-alpha may regulate hematopoiesis indirectly through release of M-CSF by stromal cells and may modulate, at least in part, the hematopoietic response to inflammation.

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A Randomized Phase II Trial of Granulocyte-Macrophage Colony-Stimulating Factor Therapy in Severe Sepsis with Respiratory Dysfunction

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/rccm.2009005 ◽

2002 ◽

Vol 166 (2) ◽

pp. 138-143 ◽

Cited By ~ 123

Author(s):

Jeffrey J. Presneill ◽

Trudi Harris ◽

Alastair G. Stewart ◽

John F. Cade ◽

John W. Wilson

Keyword(s):

Severe Sepsis ◽

Phase Ii ◽

Phase Ii Trial ◽

Colony Stimulating Factor ◽

Respiratory Dysfunction ◽

Randomized Phase Ii ◽

Factor Therapy ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

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Tubulointerstitial Macrophage Accumulation is Regulated by Sequentially Expressed Osteopontin and Macrophage Colony-Stimulating Factor: Implication for the Role of Atorvastatin

Mediators of Inflammation ◽

10.1155/mi/2006/12919 ◽

2006 ◽

Vol 2006 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Shaojiang Tian ◽

Guohua Ding ◽

Ruhan Jia ◽

Guili Chu

Keyword(s):

Treatment Group ◽

Time Course ◽

Interstitial Fibrosis ◽

Statin Treatment ◽

Histological Evaluation ◽

Colony Stimulating Factor ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor ◽

Macrophage Accumulation

Infiltration and local proliferation are known factors that contribute to tubulointerstitial macrophage accumulation. This study explored the time course of these two contributors' roles as tubulointerstitial inflammation and fibrosis progressing, and evaluated the mechanisms of the protective effect of atorvastatin. Unilateral ureteral obstructive (UUO) rats were treated with atorvastatin (10 mg/Kg) or vehicle. Expression of osteopontin (OPN) and macrophage colony-stimulating factor (M-CSF) was evaluated by RT-PCR and immunohistochemistry. Immunohistochemistry staining of ED1 was used to assess macrophage accumulation in interstitium. Histological evaluation was performed to semiquantify tubulointerstitial fibrosis. The results showed that on day 3 after UUO operation, OPN expression significantly increased and positively correlated with the number of the interstitial ED1+cells, while on day 10, M-CSF expression upregulated and correlated with interstitial ED1+cells. In atorvastatin treatment group, the increments of these two factors were attenuated significantly at the two time points, respectively. ED1+cell accumulation and fibrosis also ameliorated in the treatment group. For all the samples of UUO and treatment group on day 10, ED1+cells also correlated with interstitial fibrosis scores. The results suggest that OPN may induce the early macrophage/monocyte infiltration and M-CSF may play an important role in regulating macrophage accumulation in later stage of UUO nephropathy. Statin treatment decreases interstitial inflammation and fibrosis, and this renoprotective effect may be mediated by downregulating the expression of OPN and M-CSF.

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Distribution of receptors for granulocyte-macrophage colony-stimulating factor on immature CD34+ bone marrow cells, differentiating monomyeloid progenitors, and mature blood cell subsets

Blood ◽

10.1182/blood.v84.3.764.bloodjournal843764 ◽

1994 ◽

Vol 84 (3) ◽

pp. 764-774 ◽

Cited By ~ 42

Author(s):

AW Wognum ◽

Y Westerman ◽

TP Visser ◽

G Wagemaker

Keyword(s):

Bone Marrow ◽

Receptor Expression ◽

Colony Stimulating Factor ◽

Short Term ◽

Gm Csf ◽

Cd34 Cells ◽

Macrophage Colony Stimulating Factor ◽

Low Levels ◽

Macrophage Colony ◽

Stimulating Factor

Biotin-labeled granulocyte-macrophage colony-stimulating factor (GM- CSF), in combination with phycoerythrin-conjugated streptavidin, enabled flow cytometric analysis of specific cell-surface GM-CSF receptors on rhesus monkey bone marrow (BM) and peripheral blood (PB) cells. GM-CSF receptors were readily detected on PB monocytes and neutrophils, but not on lymphocytes. In BM, GM-CSF receptors were identified on monocyte and neutrophil precursors and on subsets of cells that expressed the CD34 antigen. CD34+ cells with high GM-CSF- receptor expression coexpressed high levels of the class II major histocompatibility antigen RhLA-DR, whereas CD34+/RhLA-DRlow cells, which represent developmentally earlier cells, were either GM-CSF- receptor negative or expressed GM-CSF receptors at very low levels. The fluorescence histogram of CD34bright/RhLA-DRdull cells stained with biotin-GM-CSF showed that at least a fraction of these cells expressed low levels of GM-CSF receptors. CD34+ cells with high GM-CSF-receptor expression, purified by cell sorting, did not form colonies in culture or proliferate in response to GM-CSF. Instead, GM-CSF stimulation resulted in terminal differentiation into adherent cells, showing that these cells represented monocyte precursors. A distinct subset of CD34+ cells expressed GM-CSF receptors at low-to-intermediate levels and proliferated strongly in the presence of GM-CSF during short-term culture, but produced very few erythroid or monomyeloid colonies after longer culture periods. Most colony-forming cells, also those responsive to GM-CSF alone, were recovered in the subset of CD34+ cells on which GM-CSF receptors were virtually undetectable. These cells showed weaker proliferation in short-term proliferation assays than the CD34+/GM-CSF-receptor-intermediate cells, consistent with an immature phenotype. The results show that GM-CSF-receptor expression is initiated in a subset of immature, CD34bright/RhLA-DRdull cells and is progressively increased during differentiation into mature granulocytes and monocytes. The method used provides a new way to deplete developmentally early CD34+ cell of differentiating granulocyte and monocyte precursor cells.

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Granulocyte/macrophage–colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects

Blood ◽

10.1182/blood-2008-05-155689 ◽

2009 ◽

Vol 113 (11) ◽

pp. 2547-2556 ◽

Cited By ~ 91

Author(s):

Kanji Uchida ◽

Koh Nakata ◽

Takuji Suzuki ◽

Maurizio Luisetti ◽

Masato Watanabe ◽

...

Keyword(s):

Healthy Subjects ◽

Healthy People ◽

Therapeutic Window ◽

Critical Threshold ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Low Levels ◽

Macrophage Colony ◽

Stimulating Factor

High levels of granulocyte/macrophage–colony-stimulating factor (GM-CSF) autoantibodies are thought to cause pulmonary alveolar proteinosis (PAP), a rare syndrome characterized by myeloid dysfunction resulting in pulmonary surfactant accumulation and respiratory failure. Paradoxically, GM-CSF autoantibodies have been reported to occur rarely in healthy people and routinely in pharmaceutical intravenous immunoglobulin (IVIG) purified from serum pooled from healthy subjects. These findings suggest that either GM-CSF autoantibodies are normally present in healthy people at low levels that are difficult to detect or that serum pooled for IVIG purification may include asymptomatic persons with high levels of GM-CSF autoantibodies. Using several experimental approaches, GM-CSF autoantibodies were detected in all healthy subjects evaluated (n = 72) at low levels sufficient to rheostatically regulate multiple myeloid functions. Serum GM-CSF was more abundant than previously reported, but more than 99% was bound and neutralized by GM-CSF autoantibody. The critical threshold of GM-CSF autoantibodies associated with the development of PAP was determined. Results demonstrate that free serum GM-CSF is tightly maintained at low levels, identify a novel potential mechanism of innate immune regulation, help define the therapeutic window for potential clinical use of GM-CSF autoantibodies to treat inflammatory and autoimmune diseases, and have implications for the pathogenesis of PAP.

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