Abstract
Interferons (IFNs) are key regulators of a number of inflammatory conditions in which neutrophils play an important role in pathology, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), where type I IFNs are implicated in disease pathology. However, IFNs are usually generated in vivo together with other cytokines that also have immunoregulatory functions, but such interactions are poorly defined experimentally. We measured the effects of type I (IFN-α) IFN, elevated in both RA and SLE, on the functions of healthy neutrophils incubated in vitro in the absence and presence of proinflammatory cytokines typically elevated in inflammatory diseases [tumour necrosis factor (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF)]. IFN-α alone had no effect on neutrophil apoptosis; however, it abrogated the anti-apoptotic effect of GM-CSF (18h, P<0·01). The enhanced stability of the anti-apoptotic protein myeloid cell leukaemia 1 (Mcl-1) and delayed activation of caspase activation normally regulated by GM-CSF were blocked by IFN-α: this effect was mediated, in part, by activation of p38 mitogen-activated protein kinase (MAPK). IFN-α alone also primed reactive oxygen species (ROS) production and maintained the transient priming effect of TNF-α for up to 4h: it also down-regulated GM-CSF- and TNF-α-activated expression of chemokine (C-X-C motif) ligand (CXCL)1, CXCL2, CXCL3, CXCL8, CCL3 and CCL4 but, in contrast, increased the expression of CXCL10. These novel data identify complex regulatory signalling networks in which type I IFNs profoundly alter the response of neutrophils to inflammatory cytokines. This is likely to have important consequences in vivo and may explain the complexity and heterogeneity of inflammatory diseases such as RA, in which multiple cytokine cascades have been activated.
Highlights
Interferons (IFNs) are a family of cytokine glycoproteins that regulate the immune response to infection by bacteria, viruses and parasites and are broadly grouped into Type-I, -II and -III, based on their receptor signalling (Platanias, 2005; Li et al, 2009)
We found that the levels of Mcl-1 after 6h incubation were significantly lower in neutrophils treated with GMCSF and IFNα compared to GM-CSF alone (Figure 1C,D, p< 0.05)
Overnight incubations (18h) of neutrophils treated with GMCSF and IFNα had significantly lower levels of pro-caspase-8 and pro-caspase-9 in the presence of IFNα compared to GM-CSF alone (Figure 1E-G, p< 0.05)
Summary
Interferons (IFNs) are a family of cytokine glycoproteins that regulate the immune response to infection by bacteria, viruses and parasites and are broadly grouped into Type-I, -II and -III, based on their receptor signalling (Platanias, 2005; Li et al, 2009). We demonstrate that co-incubation of healthy neutrophils with IFNα profoundly alters their functional responses in ways that have important consequences for understanding neutrophil phenotype in inflammatory disease. These data reveal potential complex regulatory cytokine-signalling networks that control immune function in inflammation and inflammatory disease
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