GM-CSF- and IRF4-Dependent Signaling Can Regulate Myeloid Cell Numbers and the Macrophage Phenotype during Inflammation.

Studies have demonstrated the importance of a GM-CSF→IFN regulatory factor 4 (IRF4)→CCL17 pathway, first identified in monocytes/macrophages, for arthritic pain and disease development. In this study, we further investigated the involvement of this new pathway in shaping the inflammatory response using the zymosan-induced peritonitis (ZIP) model. ZIP (8 mg of zymosan, i.

TNF and granulocyte macrophage-colony stimulating factor interdependence mediates inflammation via CCL17.

TNF and granulocyte macrophage-colony stimulating factor (GM-CSF) have proinflammatory activity and both contribute, for example, to rheumatoid arthritis pathogenesis. We previously identified a new GM-CSF→JMJD3 demethylase→interferon regulatory factor 4 (IRF4)→CCL17 pathway that is active in monocytes/macrophages in vitro and important for inflammatory pain, as well as for arthritic pain and disease. Here we provide evidence for a nexus between TNF and this pathway, and for TNF and GM-CSF interdependency.

Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation.

Data from preclinical and clinical studies have demonstrated that granulocyte macrophage colony-stimulating factor (GM-CSF) can function as a key proinflammatory cytokine. However, therapies that directly target GM-CSF function could lead to undesirable side effects, creating a need to delineate downstream pathways and mediators. In this work, we provide evidence that GM-CSF drives CCL17 production by acting through an IFN regulatory factor 4-dependent (IRF4-dependent) pathway in human monocytes, murine macrophages, and mice in vivo.

Hypoxia enhances the proliferative response of macrophages to CSF-1 and their pro-survival response to TNF.

In chronic inflammatory lesions there are increased numbers of macrophages with a possible contribution of enhanced survival/proliferation due, for example, to cytokine action; such lesions are often hypoxic. Prior studies have found that culture in low oxygen can promote monocyte/macrophage survival. We show here, using pharmacologic inhibitors, that the hypoxia-induced pro-survival response of macrophages exhibits a dependence on PI3-kinase and mTOR activities but surprisingly is suppressed by Akt and p38 MAPK activities.

Granulocyte-macrophage colony-stimulating factor is a key mediator in experimental osteoarthritis pain and disease development.

Introduction: Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be important in the development of inflammatory models of rheumatoid arthritis and there is encouraging data that its blockade may have clinical relevance in patients with rheumatoid arthritis. The aims of the current study were to determine whether GM-CSF may also be important for disease and pain development in a model of osteoarthritis.

Methods: The role of GM-CSF was investigated using the collagenase-induced instability model of osteoarthritis.

Granulocyte-macrophage colony-stimulating factor is a key mediator in inflammatory and arthritic pain.

Objectives: Better therapies are needed for inflammatory pain. In arthritis the relationship between joint pain, inflammation and damage is unclear. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is important for the progression of a number of inflammatory/autoimmune conditions including arthritis; clinical trials targeting its action in rheumatoid arthritis are underway.

Defining GM-CSF- and macrophage-CSF-dependent macrophage responses by in vitro models.

GM-CSF and M-CSF (CSF-1) induce different phenotypic changes in macrophage lineage populations. The nature, extent, and generality of these differences were assessed by comparing the responses to these CSFs, either alone or in combination, in various human and murine macrophage lineage populations. The differences between the respective global gene expression profiles of macrophages, derived from human monocytes by GM-CSF or M-CSF, were compared with the differences between the respective profiles for macrophages, derived from murine bone marrow cells by each CSF.

Extracellular proteomes of M-CSF (CSF-1) and GM-CSF-dependent macrophages.

Macrophage colony-stimulating factor (M-CSF) (also known as CSF-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have distinct effects on macrophage lineage populations, which are likely to be contributing to their functional heterogeneity. A comparative proteomic analysis of proteins released into culture media from such populations after M-CSF and GM-CSF exposure was carried out. Adherent macrophage populations, termed bone marrow-derived macrophage (BMM) and GM-BMM, were generated after treatment of murine bone marrow precursors with M-CSF and GM-CSF, respectively.

Low dose metal particles can induce monocyte/macrophage survival.

Aseptic loosening results in pain, loss of function, and ultimately prosthetic joint failure and revision surgery. The generation of wear particles from the prosthesis is a major factor in local osteolysis. We investigated the effects of such wear particles on the survival of monocytes and macrophages, populations implicated in wear particle-driven pathology.