Severe impairment of anti-cancer effect of lipoteichoic acid-related molecule isolated from a penicillin-killed Streptococcus pyogenes in toll-like receptor 4-deficient mice.
A lipoteichoic acid-related molecule (OK-PSA) isolated from OK-432, a penicillin-killed Streptococcus pyogenes, is a potent inducer of Th1 cytokines, and elicits anti-cancer effect in tumor-bearing mice. Toll-like receptor (TLR) 4 is a member of the recently identified toll-like receptor family of proteins that has been implicated in lipopolysaccharide-induced cell signaling. In the present study, we have examined the role of TLR4 for OK-PSA-induced Th1-cytokine production and anti-tumor effect by using C3H/HeJ mice in which TLR4 function is impaired. Although OK-PSA strikingly induced Th1 cytokines [interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, IL-12 and IL-18] in the splenocytes derived from control animals (C3H/HeN), OK-PSA did not induce the cytokines in the splenocytes from C3H/HeJ. Furthermore, C3H/HeJ-derived splenocytes acquired the responsiveness to OK-PSA stimulation by overexpression of TLR4 gene. Finally, OK-PSA administration significantly inhibited the tumor growth and lung metastasis of syngeneic squamous cell carcinoma cells in C3H/HeN; however, no effect of OK-PSA was observed in C3H/HeJ. These findings strongly suggest that TLR4 signaling is involved in regulating OK-PSA-induced anti-cancer immunity.
Okamoto
M
M
Second Department of Oral and Maxillofacial Surgery, Tokushima University School of Dentistry, Japan.
Oshikawa
T
T
Ohe
G
G
Nishikawa
H
H
Furuichi
S
S
Tano
T
T
Moriya
Y
Y
Saito
M
M
Sato
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D002460:Cell Line; D003470:Culture Media; D029721:Drosophila Proteins; D008070:Lipopolysaccharides / Q000737:chemistry / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010406:Penicillins / Q000494:pharmacology*; D010844:Picibanil / Q000737:chemistry*; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013297:Streptococcus pyogenes / Q000737:chemistry* / Q000187:drug effects; D013682:Teichoic Acids / Q000737:chemistry / Q000494:pharmacology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003470:Culture Media; D029721:Drosophila Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010406:Penicillins; D011956:Receptors, Cell Surface; D013682:Teichoic Acids; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D010844:Picibanil; C009900:lipoteichoic acid