Abstract
Periodontal inflammation is associated with dying cells that potentially release metabolites helping to promote inflammatory resolution. We had shown earlier that the secretome of irradiated, dying peripheral blood mononuclear cells support in vitro angiogenesis. However, the ability of the secretome to promote inflammatory resolution remains unknown. Here, we determined the expression changes of inflammatory cytokines in murine bone marrow macrophages, RAW264.7 cells, and gingival fibroblasts exposed to the secretome obtained from γ-irradiated peripheral blood mononuclear cells in vitro by RT-PCR and immunoassays. Nuclear translocation of p65 was detected by immunofluorescence staining. Phosphorylation of p65 and degradation of IκB was determined by Western blot. The secretome of irradiated peripheral blood mononuclear cells significantly decreased the expression of IL1 and IL6 in primary macrophages and RAW264.7 cells when exposed to LPS or saliva, and of IL1, IL6, and IL8 in gingival fibroblasts when exposed to IL-1β and TNFα. These changes were associated with decreased phosphorylation and nuclear translocation of p65 but not degradation of IκB in macrophages. We also show that the lipid fraction of the secretome lowered the inflammatory response of macrophages exposed to the inflammatory cues. These results demonstrate that the secretome of irradiated peripheral blood mononuclear cells can lower an in vitro simulated inflammatory response, supporting the overall concept that the secretome of dying cells promotes inflammatory resolution.
Highlights
The integrity of the tooth-supporting periodontium and the oral mucosa serving as a barrier shielding the oral tissues against the microflora of the oral cavity requires continued renewal [1,2].This renewal is achieved by the controlled dying of old or damaged cells and the concomitated replacement by new cells, a process termed homeostasis [3], a process that might be reflected by systemic levels of lipid metabolites malondialdehyde acetaldehyde [4], hormones such as vitamin D [5], and circulating cells including those of the endothelial linage [6]
We report here that the secretome of γ-irradiated peripheral blood mononuclear cells (PBMCs) corresponding to 1 × 107 cells/mL substantially decreased the expression of IL1 and IL6 in primary macrophages (Figure 1 and Figure S1) and RAW264.7 cells (Figure 2), effective after LPS or saliva treatment
Prompted by the evidence that the secretome of dying PBMCs elicits a beneficial effect in pathological conditions linked with inflammation and tissue damage such as myocarditis [28], chronic heart failure [29], spinal cord injury [30], stroke [31], and wound healing [32], and that inflammation-related catabolic changes of the periodontium are associated with the increasing presence of apoptotic macrophages [14], the goal of the work presented here was to examine whether the secretome of irradiated PBMCs can attenuate the expression of inflammatory cytokines
Summary
The integrity of the tooth-supporting periodontium and the oral mucosa serving as a barrier shielding the oral tissues against the microflora of the oral cavity requires continued renewal [1,2] This renewal is achieved by the controlled dying of old or damaged cells and the concomitated replacement by new cells, a process termed homeostasis [3], a process that might be reflected by systemic levels of lipid metabolites malondialdehyde acetaldehyde [4], hormones such as vitamin D [5], and circulating cells including those of the endothelial linage [6]. Apoptosis and senescence are the most important mechanisms to eliminate damaged cells [7,8] and the role of autophagy in the pathogenesis of periodontal disease is increasingly recognized [9] If this homeostasis is disturbed, for example in response to chronic inflammation, catabolic changes culminate in tissue atrophy as observed at sites of chronic periodontitis [10] and periimplantitis [11]. One fundamental principle to maintain homeostasis is that the dying cells release metabolites as ‘good-bye’ signals that help to maintain tissue integrity [13]
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