Regulation of Airway Inflammation by G-protein Regulatory Motif Peptides of AGS3 protein.
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 TNFα by regulating Gαi. We found that the G-protein regulatory (GPR) motif peptide in AGS3 binds to Gαi and downregulates MUC1 expression; in contrast, this motif upregulates TNFα expression. Mutated GPR Q34A peptide increased the expression of MUC1 and TGFβ but decreased the expression of TNFα 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.
Department of Microbiology, Inje University College of Medicine, Busan, Korea.
Il-Whan
IW
Choi
Department of Physiology, Kosin University College of Medicine, Busan, Korea.
Do Whan
do W
Ahn
Department of Physiology, Kosin University College of Medicine, Busan, Korea.
Jang-Kyu
JK
Choi
Department of Parasitology and Genetics, Kosin University College of Medicine, Busan, Korea.|Institute of Medicine, Kosin University College of Medicine, Busan, Korea.
Hee-Jae
HJ
Cha
Department of Parasitology and Genetics, Kosin University College of Medicine, Busan, Korea.
Mee Sun
MS
Ock
Department of Life Science, Chung-Ang University, Seoul, Korea.
EunAe
E
You
Department of Life Science, Chung-Ang University, Seoul, Korea.
SangMyung
S
Rhee
Department of Otolaryngology-Head and Neck Surgery, University of Arizona College of Medicine, Tucson, AZ, USA.
Kwang Chul
KC
Kim
Department of Biochemistry, College of Korean Medicine, Don-Eui University, Busan, Korea.
Yung Hyun
YH
Choi
Department of Physiology, Kosin University College of Medicine, Busan, Korea.|Institute of Medicine, Kosin University College of Medicine, Busan, Korea.
Kyoung Seob
KS
Song
D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000502:physiology; D015870:Gene Expression; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000502:physiology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D019718:Receptors, CXCR4 / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation
D000199:Actins; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C525615:GPSM1 protein, human; D020730:Guanine Nucleotide Dissociation Inhibitors; C508600:IL6 protein, human; D015850:Interleukin-6; D008233:Lymphotoxin-alpha; C060192:MUC1 protein, human; D018396:Mucin-1; D010446:Peptide Fragments; D019718:Receptors, CXCR4