Toll-like receptors differentially regulate GPCR kinases and arrestins in primary macrophages

作者：Loniewski Katie; Shi Yuhui; Pestka James; Parameswaran Narayanan^*

来源：Molecular Immunology, 2008, 45(8): 2312-2322.

DOI：10.1016/j.molimm.2007.11.012

• arrestin-2
• arrestin-3
• beta-arrestin
• TLR
• GPCR
• TLR4
• GRK2
• GRK5
• GRK6
• GPCR kinase
• TLR3
• TLR2
• TLR7

G-protein coupled receptor kinases (GRKs) and arrestins (ARRs) are ubiquitously distributed crucial signaling proteins that are critical in the regulation of responsiveness of G-protein coupled receptors (GPCRs). Toll-like receptors (TLRs) (class of pattern recognition receptors) play a vital role in macrophage biology and innate immunity. Because GPCR responsiveness is regulated in part by the expression levels of GRKs/ARRs, the focus of this work was to uncover potential cross-talk mechanisms between TLRs and GPCRs via regulation of GRK/ARR expression in primary mouse macrophages. We demonstrate here that activation of TLR2 and 4 (but not TLR3 and 7) significantly decrease ARR2 but not ARR3 protein levels in macrophages. Compared to this, activation of TLR2, 4, and 7 (but not TLR3) significantly decrease GRK5 and 6 protein levels. Surprisingly, GRK2 protein levels are markedly increased by TLR2, 3, 4 and 7. Mechanistically, expression of ARR2 and GRK5 are regulated at transcriptional as well as post-translational levels. Downregulation of GRK6 by LPS is regulated primarily at the post-translational level. TLR4-induced GRK2 level, however, is both transcriptionally and post-transcriptionally regulated. Our results demonstrate previously unknown crucial regulatory mechanisms that alter ARR/GRK expression levels in macrophages that might modify many, if not all, GPCR-mediated innate immune responses.

• 出版日期2008-4