CSF-1 (M-CSF) Enhances the Inflammatory Response of Fibronectin-Primed Macrophages: Pathways Involved in Activation of the Cytokine Network

Abstract

We have previously reported that the priming of thioglycollate-elicited peritoneal macrophages (PMφ), as a representative population of mononuclear phagocytes (MNP), by macrophage-colony-stimulating factor (M-CSF or CSF-1) rendered these cells more susceptible to secondary stimulation by extracellular matrix (ECM) proteins, in particular fibronectin (FN), and that at least two β1 integrins, VLA 4 (α₄β₁ or CD49d) and VLA 5 (α₅β₁ or CD49e), regulate IL-6 gene expression when PMφ come into contact with FN. In this report, we focused our attention on resident PMφ, as a more mature/differentiated MNP subpopulation. By using granulocyte-macrophage colony-stimulating factor (GM-CSF)- and IL-6-knockout (null) mice, we demonstrated that the cooperative effect between CSF-1 and FN in IL-6 release was a result of a sequential stimulation of the GM-CSF, but not the TNF-α, gene via interaction with VLA 5. We also showed that regardless of the presence or absence of CSF-1 or FN, IL-6 inhibits GM-CSF and TNF-α gene expression in an autocrine manner. The observed effects were specific because CSF-1 enhanced VLA 5 expression and blocking FN-treated resident PMφ in vitro with VLA 5 monoclonal antibodies inhibited the IL-6 response. We found that treatment of resident PMφ with the protein kinase C inhibitor, staurosporine, and the activator, phorbol myristate acetate (PMA), resulted in marked modulation of either FN- or FN/CSF-1-induced cytokine release. An increased level of VLA 5 expression was observed in PMA-treated resident PMφ. We concluded that in inflammatory processes, CSF-1 drives a number of pathways involved in the regulation of the expression of several genes and renders MNP highly susceptible to stimulation by ECM proteins that transform the MNP into secretory inflammatory cells.

Lack of IL-6 augments inflammatory response but decreases vascular permeability in bacterial meningitis

“…GM-CSF can directly act on PMN by modulating the surface expression of adhesion molecules and increasing neutrophil adherence to the endothelium (Arnaout et al, 1986). It was shown that GM-CSF can induce the expression of IL-6 in monocytes and microglia (Suzumura et al, 1996) and that vice versa IL-6 can inhibit GM-CSF gene expression (Kremlev et al, 1998), presenting a negative feedback system which might explain the fact that the basal GM-CSF mRNA level in uninfected IL-6 ±/± mice was more than twice that in WT controls. Therefore, it was surprising that the increase in GM-CSF mRNA expression was attenuated in infected IL-6 ±/± mice, compared with infected WT mice.…”

Allogeneic Adipose-Derived Stem Cells Mitigate Acute Radiation Syndrome by the Rescue of Damaged Bone Marrow Cells from Apoptosis

“…MCSF expresses high levels and stimulates the expression of other inflammatory molecules during stress or inflammation. 68 Angiogenesis is essential for blood circulation and communication between tissues and cells. Exotoxin is a hematopoietic stem cell-derived proangiogenic factor necessary for neovascularization and reduces the inflammation.…”

Colony-Stimulating Factor 1 Receptor (CSF1R) Activates AKT/mTOR Signaling and Promotes T-Cell Lymphoma Viability

“…However, our findings also show that autocrine activation of CSF1R promotes lymphoma growth in the absence of exogenous CSF1. CSF1 is posttranslationally modified and often retained within the extracellular matrix, and may be difficult to detect in plasma (66,67), and could explain why CSF1 was rarely detected in plasma from TCL patients (data not shown). Future studies will be needed in a larger cohort of patients to examine the extent to which CSF1R expression is associated with disease natural history or response to therapy.…”