Cytokine induction by the hepatitis B virus capsid in macrophages is facilitated by membrane heparan sulfate and involves TLR2.
The hepatitis B virus (HBV) core Ag (HBcAg) serves as the structural subunit of the highly immunogenic capsid shell. HBcAg harbors a unique arginine-rich C terminus that was implicated in immune responses induced by the capsid. In this study, we examined the capacity of the HBV capsid to induce proinflammatory and regulatory cytokines in human THP-1 macrophages and the possible underlying mechanism. Full-length HBc capsids, but not HBc-144 capsids lacking the arginine-rich domain of HBcAg, efficiently bound differentiated THP-1 macrophages and strongly induced TNF-alpha, IL-6, and IL-12p40. Capsid binding to macrophages and cytokine induction were independent of the RNA associated with the arginine-rich domain. Soluble heparin and heparan sulfate but not chondroitin sulfates greatly diminished cytokine induction through inhibition of capsid binding to THP-1 macrophages. Furthermore, serine phosphorylation in the arginine-rich domain modulates capsid binding to macrophages and the cytokine response. Induction of cytokines by the capsid involved activation of NF-kappaB, ERK-1/2, and p38 MAPK and did not require endosomal acidification. Finally, NF-kappaB activation by the capsid in HEK 293 cells specifically required expression of TLR2 and was compromised by soluble heparin. Thus, cytokine induction by the HBV capsid in macrophages is facilitated by interaction of its arginine-rich domain with membrane heparan sulfate and involves signaling through TLR2.
Cooper
Arik
A
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Tal
Guy
G
Lider
Ofer
O
Shaul
Yosef
Y
D000818:Animals; D016466:CHO Cells; D002213:Capsid / Q000502:physiology*; D002478:Cells, Cultured; D006224:Cricetinae; D016207:Cytokines / Q000096:biosynthesis*; D006497:Heparan Sulfate / Q000502:physiology*; D006512:Hepatitis B Core Antigens / Q000494:pharmacology*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016207:Cytokines; D006497:Heparan Sulfate; D006512:Hepatitis B Core Antigens; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D012694:Serine; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C495342:TLR2 protein, human