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* Department of Laboratory Medicine, Clinical Center;
Office of Biotechnology Activities, Office of Science Policy, Office of the Director; and
Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
Scavenger receptor CD36 mediates Staphylococcus aureus phagocytosis and initiates TLR2/6 signaling. We analyzed the role of CD36 in the uptake and TLR-independent signaling of various bacterium, including Escherichia coli, Klebsiella pneumoniae, Salmonella typhimurium, S. aureus, and Enterococcus faecalis. Expression of human CD36 in HeLa cells increased the uptake of both Gram-positive and Gram-negative bacteria compared with the control mock-transfected cells. Bacterial adhesion was associated with pathogen phagocytosis. Upon CD36 transfection, HEK293 cells, which demonstrate no TLR2/4 expression, acquired LPS responsiveness as assessed by IL-8 production. The cells demonstrated a marked 5- to 15-fold increase in cytokine release upon exposure to Gram-negative bacteria, while the increase was much smaller (1.5- to 3-fold) with Gram-positive bacteria and lipoteichoic acid. CD36 down-regulation utilizing CD36 small interfering RNA reduced cytokine release by 40–50% in human fibroblasts induced by both Gram-negative and Gram-positive bacteria as well as LPS. Of all MAPK signaling cascade inhibitors tested, only the inhibitor of JNK, a stress-activated protein kinase, potently blocked E. coli/LPS-stimulated cytokine production. NF-
B inhibitors were ineffective, indicating direct TLR-independent signaling. JNK activation was confirmed by Western blot analyses of phosphorylated JKN1/2 products. Synthetic amphipathic peptides with an 
-helical motif were shown to be efficient inhibitors of E. coli- and LPS-induced IL-8 secretion as well as JNK1/2 activation/phosphorylation in CD36-overexpressing cells. These results indicate that CD36 functions as a phagocytic receptor for a variety of bacteria and mediates signaling induced by Gram-negative bacteria and LPS via a JNK-mediated signaling pathway in a TLR2/4-independent manner.
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1 This research was supported by the Intramural Research Programs of the Clinical Center, National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Thomas L. Eggerman, Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 6707 Democracy Boulevard, Room 697, MSC 5460, Bethesda, MD 20892-5460. E-mail address: Eggermant{at}niddk.nih.gov; cc: abocharov{at}mail.cc.nih.gov
3 Abbreviations used in this paper: oxLDL, oxidized LDL; hCD36, human CD36; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LTA, lipoteichoic acid; MEK, MAP kinase kinase; siRNA, small interfering RNA.
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  L. K. Erdman, G. Cosio, A. J. Helmers, D. C. Gowda, S. Grinstein, and K. C. Kain CD36 and TLR Interactions in Inflammation and Phagocytosis: Implications for Malaria J. Immunol., November 15, 2009; 183(10): 6452 - 6459. [Abstract] [Full Text] [PDF]
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 R. L. Silverstein and M. Febbraio CD36, a Scavenger Receptor Involved in Immunity, Metabolism, Angiogenesis, and Behavior Sci. Signal., May 26, 2009; 2(72): re3 - re3. [Abstract] [Full Text] [PDF]
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