Regulation of Airway Inflammation by G-protein Regulatory Motif Peptides of AGS3 protein.

ABSTRACT: Respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and lung infections have critical consequences on mortality and morbidity in humans. The aims of the present study were to examine the mechanisms by which CXCL12 affects MUC1 transcription and airway inflammation, which depend on activator of G-protein signaling (AGS) 3 and to identify specific molecules that suppress CXCL12-induced airway inflammation by acting on G-protein-coupled receptors. Herein, AGS3 suppresses CXCL12-mediated upregulation of MUC1 and TNF? by regulating G?i. We found that the G-protein regulatory (GPR) motif peptide in AGS3 binds to G?i and downregulates MUC1 expression; in contrast, this motif upregulates TNF? expression. Mutated GPR Q34A peptide increased the expression of MUC1 and TGF? but decreased the expression of TNF? and IL-6. Moreover, CXCR4-induced dendritic extensions in 2D and 3D matrix cultures were inhibited by the GPR Q34A peptide compared with a wild-type GPR peptide. The GPR Q34A peptide also inhibited CXCL12-induced morphological changes and inflammatory cell infiltration in the mouse lung, and production of inflammatory cytokines in bronchoalveolar lavage (BAL) fluid and the lungs. Our data indicate that the GPR motif of AGS3 is critical for regulating MUC1/Muc1 expression and cytokine production in the inflammatory microenvironment.

SUBMITTER: Choi IW 

PROVIDER: S-EPMC4895231 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature