OK‐432‐stimulated chemokine secretion from human monocytes depends on MEK1/2, and involves p38 MAPK and NF‐κB phosphorylation, in vitro

Abstract

Interaction between the immune system and cancer cells allows for the use of biological response modifiers, like OK-432, in cancer therapy. We have studied the involvement of monocytes (MOs) in the immune response to OK-432 by examining MCP-1, MIP-1α and MIP-1β secretion, in vitro. OK-432-induced IL-6/TNF-α secretion has previously been shown to depend on mitogen-activated protein kinases (MAPKs) ERK1/2 and p38, and we therefore investigated the role of these MAPKs in OK-432-induced chemokine secretion. Here we demonstrate that pharmacological MEK1/2 kinase inhibition generally impaired chemokine secretion from MOs, whereas p38 MAPK inhibition in particular reduced MIP-1α production. Furthermore, simultaneous inhibition of MEK1/2 and Syk kinase was seen to have an additive impact on reduced MCP-1, MIP-1α and MIP-1β secretion. Based on single cell flow cytometry analyses, OK-432, lipoteichoic acid (LTA) and lipopolysaccharide (LPS) were seen to induce p38 MAPK and NF-κB phosphorylation in MOs with different time kinetics. LTA and LPS have been shown to induce ERK1/2 phosphorylation, whereas the levels of phosphorylated ERK1/2 remained constant following OK-432 treatment at the time points tested. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns, and we demonstrate increased TLR2 cell surface levels on the MO population, most profoundly following stimulation with LTA and OK-432. Together these results indicate that modulation of MEK1/2 and p38 MAPK signalling could affect the response to OK-432 treatment, having the potential to improve its therapeutic potential within cancer and lymphangioma treatment.

Peripheral blood monocyte and T‐lymphocyte activation levels at diagnosis predict long‐term survival in head and neck squamous cell carcinoma patients

“…Monocytes are members of the MNP compartment and precursors of macrophages. MNP are versatile cells , which, e.g., secrete different cytokines following activation . Monocyte function is classically studied by measuring cytokine secretion after in vitro stimulation by LPS .…”

“…MNP are versatile cells , which, e.g., secrete different cytokines following activation . Monocyte function is classically studied by measuring cytokine secretion after in vitro stimulation by LPS . LPS stimulation triggers secretion of pro‐inflammatory interleukins (IL‐1β, IL‐6, TNF‐α) and modulates chemokine (MCP‐1) secretion .…”

In Vitro-Stimulated IL-6 Monocyte Secretion and In Vivo Peripheral Blood T Lymphocyte Activation Uniquely Predicted 15-Year Survival in Patients with Head and Neck Squamous Cell Carcinoma

“…Monocytes are members of the MNP system [4], which secrete such cytokines in particular following activation [24, 25]. Monocyte function may be assessed by measuring cytokine secretion after in vitro stimulation of the TLR-4 receptor [26].…”

“…Monocyte function may be assessed by measuring cytokine secretion after in vitro stimulation of the TLR-4 receptor [26]. Such stimulation promotes the secretion in particular of pro-inflammatory interleukins (IL-1β, IL-6, TNF-α) [25], and modulates chemokine (MIP-1α/β, MCP-1) secretion [24]. …”

Levistilide A Ameliorates NLRP3 Expression Involving the Syk-p38/JNK Pathway and Peripheral Obliterans in Rats

“…Syk is also required for cytokine production with MyD88 adaptor protein pathways [ 30 ]. Numerous studies have demonstrated that Syk-mediated mitogen-activated protein kinases play a vital role in the expression of inflammatory genes [ 31 – 33 ]. Syk mediates NLRP3 inflammasome activation [ 34 – 36 ].…”