Paracrine in vivo inhibitory effects of adipose tissue-derived mesenchymal stromal cells in the early stages of the acute inflammatory response.
OBJECTIVE
Excessive or unresolved inflammation leads to tissue lesions. Adipose tissue-derived mesenchymal stromal cells (AMSCs) have shown protective effects that may be dependent on the modulation of inflammation by secreted factors.


METHODS
We used the zymosan-induced mouse air pouch model at two time points (4 h and 18 h) to evaluate the in vivo effects of AMSCs and their conditioned medium (CM) on key steps of the early inflammatory response. We assessed the effects of AMSCs and CM on leukocyte migration and myeloperoxidase activity. The levels of chemokines, cytokines and eicosanoids in exudates were measured by use of enzyme-linked immunoassay or radio-immunoassay. In addition, the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES-1) was studied by use of Western blotting and the phosphorylation of p65 nuclear factor-κB (NF-κB) by immunofluorescence.


RESULTS
All inflammatory parameters were significantly reduced by CM and AMSCs to a similar extent at 4 h after zymosan injection with lower effects at 18 h. The observed inhibition of leukocyte migration was associated with reduced levels of chemokines and leukotriene B4. Interleukin-1β, interleukin-6, tumor necrosis factor-α and tumor necrosis factor-stimulated gene 6 levels were significantly decreased. The downregulation of mPGES-1 was associated with inhibition of prostaglandin E2 production. Our results suggest that these anti-inflammatory effects are related, in part, to the inhibition of NF-κB activation.


CONCLUSIONS
AMSCs dampen the early process of inflammation in the zymosan-induced mouse air pouch model through paracrine mechanisms. These results support the potential utility of these cells as a source of novel treatment approaches for inflammatory pathologies.
Department of Pharmacology and IDM, University of Valencia, Valencia, Spain.
María Carmen
MC
Carceller
Department of Pharmacology and IDM, University of Valencia, Valencia, Spain; Department of Chemistry, Biochemistry and Molecular Biology, Cardenal Herrera-CEU University, Valencia, Spain.
María Isabel
MI
Guillén
Department of Pharmacology and IDM, University of Valencia, Valencia, Spain.
María Luisa
ML
Ferrándiz
Department of Pharmacology and IDM, University of Valencia, Valencia, Spain. Electronic address: maria.j.alcaraz@uv.es.
María José
MJ
Alcaraz
D000273:Adipose Tissue / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis; D007962:Leukocytes / Q000502:physiology; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D019899:Paracrine Communication; D000071876:Prostaglandin-E Synthases; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015054:Zymosan / Q000494:pharmacology
D017077:Culture Media, Conditioned; D016207:Cytokines; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; D015054:Zymosan; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone
adipose tissue–derived stem cells; conditioned medium; inflammation; mouse air pouch