Apolipoprotein A-I mimetic 4F alters the function of human monocyte-derived macrophages.

نویسندگان

  • Lesley E Smythies
  • C Roger White
  • Akhil Maheshwari
  • M N Palgunachari
  • G M Anantharamaiah
  • Manjula Chaddha
  • Ashish R Kurundkar
  • Geeta Datta
چکیده

HDL and its major protein component apolipoprotein A-I (apoA-I) exert anti-inflammatory effects, inhibit monocyte chemotaxis/adhesion, and reduce vascular macrophage content in inflammatory conditions. In this study, we tested the hypothesis that the apoA-I mimetic 4F modulates the function of monocyte-derived macrophages (MDMs) by regulating the expression of key cell surface receptors on MDMs. Primary human monocytes and THP-1 cells were treated with 4F, apoA-I, or vehicle for 7 days and analyzed for expression of cell surface markers, adhesion to human endothelial cells, phagocytic function, cholesterol efflux capacity, and lipid raft organization. 4F and apoA-I treatment decreased the expression of HLA-DR, CD86, CD11b, CD11c, CD14, and Toll-like receptor-4 (TLR-4) compared with control cells, suggesting the induction of monocyte differentiation. Both treatments abolished LPS-induced mRNA for monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1 (MIP-1), regulated on activation, normal T-expressed and presumably secreted (RANTES), IL-6, and TNF-alpha but significantly upregulated LPS-induced IL-10 expression. Moreover, 4F and apoA-I induced a 90% reduction in the expression of CD49d, a ligand for the VCAM-1 receptor, with a concurrent decrease in monocyte adhesion (55% reduction) to human endothelial cells and transendothelial migration (34 and 27% for 4F and apoA-I treatments) compared with vehicle treatment. In addition, phagocytosis of dextran-FITC beads was inhibited by 4F and apoA-I, a response associated with reduced expression of CD32. Finally, 4F and apoA-I stimulated cholesterol efflux from MDMs, leading to cholesterol depletion and disruption of lipid rafts. These data provide evidence that 4F, similar to apoA-I, induces profound functional changes in MDMs, possibly due to differentiation to an anti-inflammatory phenotype.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Regulation of pattern recognition receptors by the apolipoprotein A-I mimetic peptide 4F.

OBJECTIVE The apolipoprotein A-I (apoA-I) mimetic peptide 4F favors the differentiation of human monocytes to an anti-inflammatory phenotype and attenuates lipopolysaccharide (LPS)-induced inflammatory responses. We investigated the effects of LPS on the Toll-like receptor (TLR) signaling pathway in 4F-differentiated monocyte-derived macrophages. METHODS AND RESULTS Monocyte-derived macrophag...

متن کامل

DIFFERENTIATION OF MONOCYTE DERIVED DENDRITIC CELLS IN SERUM FREE CONDITIONS

Human peripheral blood monocytes (HPBM) were cultured in the absence of human serum and were converted into a state exhibiting a high accessory function expressed by their ability of supporting lymphocyte proliferation. After a prolonged culture in serum free media the monocyte derived cells were highly viable, increased in size and developed veils and dendritiform elongatio'l1s. Paralleli...

متن کامل

Apolipoprotein A-I mimetic peptide 4F suppresses tumor-associated macrophages and pancreatic cancer progression

Pancreatic cancer is an aggressive malignancy that is unresponsive to conventional radiation and chemotherapy. Therefore, development of novel immune therapeutic strategies is urgently needed. L-4F, an Apolipoprotein A-I (ApoA-I) mimetic peptide, is engineered to mimic the anti-inflammatory and anti-oxidative functionalities of ApoA-I. In this work, H7 cells were orthotopically implanted in C57...

متن کامل

Oral D-4F Causes Formation of Pre- High-Density Lipoprotein and Improves High-Density Lipoprotein–Mediated Cholesterol Efflux and Reverse Cholesterol Transport From Macrophages in Apolipoprotein E–Null Mice

Background—These studies were designed to determine the mechanism of action of an oral apolipoprotein (apo) A-I mimetic peptide, D-4F, which previously was shown to dramatically reduce atherosclerosis in mice. Methods and Results—Twenty minutes after 500 g of D-4F was given orally to apoE-null mice, small cholesterolcontaining particles (CCPs) of 7 to 8 nm with premobility and enriched in apoA-...

متن کامل

An apolipoprotein A-I mimetic targets scavenger receptor A on tumor-associated macrophages

Tumor-associated macrophages polarize toward an M2 phenotype and express scavenger receptor A (SRA), hence promoting tumor progression. We demonstrated that SRA can be therapeutically targeted in vivo with the small peptide inhibitor 4F to prevent metastatic spread. Beyond our study, 4F is emerging as a promising anticancer agent.

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • American journal of physiology. Cell physiology

دوره 298 6  شماره 

صفحات  -

تاریخ انتشار 2010