High glucose up-regulates lipopolysaccharide-stimulated inflammatory cytokine production via c-jun N-terminal kinase in the monocytic cell line THP-1.
Diabetic subjects are susceptible to atherosclerosis. It has been postulated that inflammation plays a crucial role in atherogenesis. Since previous studies suggested persistent low-grade infection by Gram-negative bacteria such as Chlamydia spp. and/or periodontal infection is associated with increased atherogenesis among diabetic subjects, we hypothesized that macrophages under hyperglycemia respond to lipopolysaccharide (LPS) challenge in a more exaggerated manner than under normal glucose conditions. Therefore, we examined cytokine productivity and associated signal transduction molecules in LPS-stimulated the monocytic cell line THP-1, under conditions of hyperglycemia. Differentiated THP-1 cells were cultured under normal and high glucose conditions without fetal bovine serum, and were stimulated with Escherichia coli LPS in the presence of LPS binding protein. Following stimulation, activated signal transduction molecules were detected by protein microarray and confirmed thereafter. Results indicated that c-jun N-terminal kinase (JNK) was highly-phosphorylated at high glucose concentrations, and this was confirmed by Western-immunoblotting. Tumor necrosis factor-alpha and monocyte chemo-attractant protein-1 production were significantly enhanced under these conditions. SP600125, a selective inhibitor of JNK, dose-dependently suppressed the production of these cytokine. Therefore, we suggest that this may be one of the mechanisms by which sub-clinical infection by Gram-negative bacteria promotes atherosclerosis in diabetic subjects.
Iwata
Hirotaka
H
Department of Pathophysiology - Periodontal Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Soga
Yoshihiko
Y
Meguro
Michio
M
Yoshizawa
Sayuri
S
Okada
Yuka
Y
Iwamoto
Yoshihiro
Y
Yamashita
Akiko
A
Takashiba
Shogo
S
Nishimura
Fusanori
F
D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics; D018946:Chemokine CCL5 / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation; D053583:Interleukin-1beta / Q000235:genetics; D007376:Interleukin-2; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009000:Monocytes; D020411:Oligonucleotide Array Sequence Analysis; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D016207:Cytokines; D053583:Interleukin-1beta; D007376:Interleukin-2; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose