Differential roles of Toll-like receptors in the elicitation of proinflammatory responses by macrophages.
BACKGROUND
Mammalian Toll-like receptor (TLR) proteins are pattern recognition receptors for a diverse array of bacterial and viral products. Gram negative bacterial lipopolysaccharide (LPS) activates cells through TLR4, whereas the mycobacterial cell wall glycolipids, lipoarabinomannan (LAM) and mannosylated phosphatidylinositol (PIM), activate cells through TLR2. Furthermore, short term culture filtrates of M. tuberculosis bacilli contain a TLR2 agonist activity, termed soluble tuberculosis factor (STF), that appears to be PIM. It was recently shown that stimulation of RAW264.7 murine macrophages by LPS, LAM, STF, and PIM rapidly activated NF-kappaB, AP1, and MAP kinases.


RESULTS
This study shows that signalling by TLR2 and TLR4 also activates the protein kinase Akt, a downstream target of phosphatidylinositol-3'-kinase (PI-3-K). This finding suggests that activation of PI-3-K represents an additional signalling pathway induced by engagement of TLR2 and TLR4. Subsequently, the functional responses induced by the different TLR agonists were compared. LPS, the mycobacterial glycolipids, and the OspC lipoprotein (a TLR2 agonist) all induced macrophages to secrete tumour necrosis factor alpha (TNFalpha), whereas only LPS could induce nitric oxide (NO) secretion. Human alveolar macrophages also exhibited a distinct pattern of cellular response after stimulation with TLR2 and TLR4 agonists. Specifically, LPS induced TNFalpha, MIP-1beta, and RANTES production in these cells, whereas the TLR2 agonists induced only MIP-1beta production.


CONCLUSIONS
Together, these data show that different TLR proteins mediate the activation of distinct cellular responses, despite their shared ability to activate NF-kappaB, AP1, MAP kinases, and PI-3-K.
Jones
B W
BW
Pulmonary Centre, Boston University School of Medicine, MA 02118-2394, USA.
Heldwein
K A
KA
Means
T K
TK
Saukkonen
J J
JJ
Fenton
M J
MJ
D000818:Animals; D000953:Antigens, Protozoan; D050976:Basic-Leucine Zipper Transcription Factors; D002460:Cell Line; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000494:pharmacology; D029721:Drosophila Proteins; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000502:physiology*; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis; D009569:Nitric Oxide / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015800:Protozoan Proteins / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D030262:Soybean Proteins; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000953:Antigens, Protozoan; D050976:Basic-Leucine Zipper Transcription Factors; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; C114565:STF1 protein, Glycine max; D030262:Soybean Proteins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C095023:antigen PIM, Theileria parva; C050016:lipoarabinomannan; D009569:Nitric Oxide; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases