Abstract
Cytoglobin (Cygb) is a hexacoordinate protein, associated with the transport of oxygen, nitric oxide scavenging, tumor suppression and protection against oxidative stress and inflammation. This protein is expressed in brain areas including the preoptic area (POA) of the anterior hypothalamus, the region responsible for the regulation of body temperature. In this study, we show that Cygb is upregulated in the rat hypothalamus 2.5 h and 5 h after intravenous administration of lipopolysaccharide (LPS). We investigated the effect of treatment with Cygb in POA primary cultures stimulated with LPS for 4 h. The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were measured and the results showed that Cygb reduced the concentrations of both cytokines. We further observed a decrease in immunoreactivity of the inflammatory transcription factor nuclear factor-κB (NF-κB), but not NF-IL6 and STAT3, in the nucleus of Cygb-treated POA cells. These findings suggest that Cygb attenuates the secretion of IL-6 and TNF-α in LPS-stimulated POA primary cultures via inhibition of the NF-κB signaling pathway, indicating that this protein might play an important role in the control of neuroinflammation and fever.
Highlights
Systemic administration of lipopolysaccharide (LPS) induces a number of brain-controlled sickness responses, such as anorexia, adipsia, reduced locomotor activity, and fever (Dantzer et al, 1998; Damm et al, 2013)
Using high-resolution mass spectrometry-based quantitative proteomics, we recently demonstrated that during LPS and PG E2-induced fever an orchestrated response, involving changes of several proteins associated with inflammatory and metabolic pathways, occurs in the hypothalamus of rats (Firmino et al, 2018)
We demonstrated the anti-neuroinflammatory effect of Cygb in LPS-activated preoptic area (POA)-cells by attenuation of pro-inflammatory cytokine secretion by inhibition of the nuclear factorκB (NF-κB) pathway
Summary
Systemic administration of lipopolysaccharide (LPS) induces a number of brain-controlled sickness responses, such as anorexia, adipsia, reduced locomotor activity, and fever (Dantzer et al, 1998; Damm et al, 2013). LPS binds to the Toll-like receptor (TLR) member TLR4 in cells of both the peripheral and central nervous system, triggering intracellular cascades of events These include activation of pro-inflammatory transcription factors, and production and release of several mediators, such as cytokines, chemokines, and prostaglandins (PGs), which are implicated in the aforementioned brain-controlled sickness responses (Damm et al, 2013; Roth and Blatteis, 2014; Zampronio et al, 2015). In addition to the proteins related to these well-known inflammatory pathways, we have identified a distinct protein that is not directly associated with any of these classical pathways, but significantly increases after induction of fever by both LPS and by PGE2 This protein, named cytoglobin (Cygb), shows features that support its potential involvement in neuroinflammation and fever regulation
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