Regulation of lipopolysaccharide-induced inflammatory response and endotoxemia by beta-arrestins.
Beta-arrestins are scaffolding proteins implicated as negative regulators of TLR4 signaling in macrophages and fibroblasts. Unexpectedly, we found that beta-arrestin-1 (beta-arr-1) and -2 knockout (KO) mice are protected from TLR4-mediated endotoxic shock and lethality. To identify the potential mechanisms involved, we examined the plasma levels of inflammatory cytokines/chemokines in the wild-type (WT) and beta-arr-1 and -2 KO mice after lipopolysaccharide (LPS, a TLR4 ligand) injection. Consistent with lethality, LPS-induced inflammatory cytokine levels in the plasma were markedly decreased in both beta-arr-1 and -2 KO, compared to WT mice. To further explore the cellular mechanisms, we obtained splenocytes (separated into CD11(b+) and CD11(b-) populations) from WT, beta-arr-1, and -2 KO mice and examined the effect of LPS on cytokine production. Similar to the in vivo observations, LPS-induced inflammatory cytokines were significantly blocked in both splenocyte populations from the beta-arr-2 KO compared to the WT mice. This effect in the beta-arr-1 KO mice, however, was restricted to the CD11(b-) splenocytes. Our studies further indicate that regulation of cytokine production by beta-arrestins is likely independent of MAPK and IkappaBalpha-NFkappaB pathways. Our results, however, suggest that LPS-induced chromatin modification is dependent on beta-arrestin levels and may be the underlying mechanistic basis for regulation of cytokine levels by beta-arrestins in vivo. Taken together, these results indicate that beta-arr-1 and -2 mediate LPS-induced cytokine secretion in a cell-type specific manner and that both beta-arrestins have overlapping but non-redundant roles in regulating inflammatory cytokine production and endotoxic shock in mice.
Porter
Katie J
KJ
Department of Physiology and Division of Pathology, Michigan State University, East Lansing, Michigan 48824, USA.
Gonipeta
Babu
B
Parvataneni
Sitaram
S
Appledorn
Daniel M
DM
Patial
Sonika
S
Sharma
Deepika
D
Gangur
Venugopal
V
Amalfitano
Andrea
A
Parameswaran
Narayanan
N
D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D018845:CD11 Antigens / Q000378:metabolism; D018929:Cell Culture Techniques; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019446:Endotoxemia / Q000378:metabolism*; D005786:Gene Expression Regulation; D007249:Inflammation / Q000139:chemically induced*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
C000605255:Arrb1 protein, mouse; D019390:Arrestins; D018845:CD11 Antigens; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020929:Mitogen-Activated Protein Kinase Kinases