MAPKs ERK and p38, but not JNK Phosphorylation, Modulate IL‐6 and TNF‐α Secretion Following OK‐432 In Vitro Stimulation of Purified Human Monocytes

Abstract

Interaction between the immune system and cancer allows for the use of biological response modifiers, e.g. OK‐432, in cancer therapy. OK‐432, penicillin‐killed Streptococcus pyogenes, is used in treating carcinomas, but also lymphangiomas. We have studied the role of monocytes (MOs) in the immune response to OK‐432 by examining IL‐6 and tumour necrosis factor (TNF)‐α secretion after in vitro MO stimulation with OK‐432, to some extent in comparison with lipoteichoic acid (LTA) and lipopolysaccharide (LPS). LTA stimulation of whole blood gave IL‐6 but not TNF‐α secretion, as previously shown with OK‐432 stimulation, whereas both cytokines were secreted following LPS stimulation. Addition of the MAPK kinase (MAPKK) MEK inhibitor U0126 inhibited IL‐6/TNF‐α secretion in a dose‐dependent manner. Flow cytometry and to some extent Western blot (Wb) analyses showed that MAPK ERK, located downstream of MEK1/2, is predominantly phosphorylated at isolation from peripheral blood. Addition of the p38 MAP kinase inhibitor SB202190 decreased MO IL‐6/TNF‐α production upon OK‐432 stimulation in a dose‐dependent manner. Addition of the MAPK JNK inhibitor SP600125 did not systematically change the MO IL‐6/TNF‐α OK‐432 response. Flow cytometry showed that when stimulating the MOs before isolation from blood, LPS yielded ERK phosphorylation and LPS/LTA p38 phosphorylation, whereas OK‐432 had no effects on phosphorylation levels. In conclusion, we have shown that OK‐432 resembles TLR2 more than TLR4 stimulation of MOs and depends on MAPKK MEK and MAPK p38, but not on JNK phosphorylation. The MEK and p38 MO OK‐432 stimulation dependence is possibly related to the differentiation of cells of the MO lineage.

Bacterial flagellin induces IL-6 expression in human basophils

“…Consistent with our results, penicillin-killed Streptococcus pyogenes-induced IL-6 production was also found to be mediated by p38 kinase and ERK pathways in monocytes (Olsnes et al, 2011). In addition, the activation of p38 kinase and ERK was essential for TNF-␣-induced IL-6 production in human primary mesangial and proximal tubular cells (Leonard et al, 1999).…”

TLR7 Engagement on Dendritic Cells Enhances Autoreactive Th17 Responses via Activation of ERK

“…Inhibition of ERK induced a trend toward reduced IL-6 expression, but it was without statistical significance in our system. This observation was unexpected, because previous reports showed that ERK activation induced by PGN or ok-432 significantly upregulated IL-6 expression in DCs or human monocytes (36,51). In response to CL097, MAPKs are phosphorylated and activate the transcription factor AP-1 (52), which can enhance the activation of IL-23, IL-1b, and IL-6 promoters, resulting in increased expression of IL-23, IL-1b, and IL-6 in DCs.…”

The protection of Rhein lysinate to liver in diabetic mice induced by high-fat diet and streptozotocin

“…Therefore, we conclude that inflammatory factors (TNF-a and IL-6) play a role in the progression of fatty liver in diabetic mice and that RHL administration reduces the production of inflammatory factors and thus protects the liver of diabetic mice. In addition, it was reported that ERK can modulate TNF-a and IL-6 secretion (Olsnes et al 2011). In this study, we observed that liver protection was also associated with improved hyperlipemia and decreased the activities of ERK1/2 and SREBP-1c.…”