Peroxisome proliferator-activated receptor gamma prevents activation of RBL-2H3 cells by inhibiting FcεRI-mediated signal transduction.

Background: Mast cells are essential contributors to the pathophysiology of allergic diseases. Peroxisome proliferator-activated receptor gamma (PPAR-γ) has recently been identified as being involved in the anti-inflammatory response by inhibiting mast cell activation.

Method: In this study, the PPAR-γ agonist pioglitazone (PIO) was employed to evaluate the effects of PPAR-γ on the degranulation and production of pro-inflammatory mediators in RBL-2H3 cells. Meanwhile, differentially expressed genes (DEGs) were characterised in mast cells exposed to PIO, and pathway enrichment analysis were conducted. Furthermore, we conducted validation to confirm the involvement of PPAR-γ signaling pathways in the FcεRI-mediated signal transduction in mast cells.

Results: Administration of PIO significantly reduced the release of β-hexosaminidase and the mRNA expression levels of pro-inflammatory cytokines induced by the cross-linking of FcεRIs expressed on the surface of RBL-2H3 cells. A total of 24 DEGs were identified between RBL-2H3 cells treated with and without PIO, and there were 15 up-regulated and 9 down-regulated. GO and KEGG analyses revealed that the immune system, signal transduction, infectious disease, and signaling molecules and interactions were the most enriched annotations. According to PPI network analysis, most DEGs interacted with PPAR-γ. PPAR-γ agonist could activate PPAR-γ and NRF2 signaling pathways in resting RBL-2H3 cells. The protein expression levels of PPAR-γ, Cpt1a, and Acsl4 were greatly upregulated in activated RBL-2H3 cells mediated by FcεRI aggregation. Moreover, the suppressive effects of PPAR-γ agonist on degranulation and phosphorylation levels of FcεRI-mediated signaling molecules in RBL-2H3 cells were PPAR-γ-dependent.

Conclusion: These data demonstrate that PPAR-γ inhibits FcεRI-mediated mast cell activation by modulating intracellular-specific signal transduction in a PPAR-γ-dependent manner.