Coactivation of TLR4 and TLR2/6 coordinates an additive augmentation on IL-6 gene transcription via p38MAPK pathway in U937 mononuclear cells

Abstract

Studies have demonstrated that TLR4 and TLR2 expression by monocytes and the blood levels of TLR4 and TLR2 ligand in diabetic patients are significantly incased compared to nondiabetic patients, indicating that more monocytes in diabetic patients may have coactivation of TLR4 and TLR2. Although it has been shown that either TLR4 or TLR2 activation leads to increased expression of proinflammatory cytokines, the effect of coactivation of TLR2 and TLR4 in mononuclear cells on proinflammatory cytokine expression and the underlying molecular mechanisms remain largely unknown. In this study, we found that while TLR1, TLR2, TLR4 and TLR6 were expressed by U937 mononuclear cells, TLR4 was expressed at the highest level. Interestingly, results showed that while activation of either TLR4 or TLR2/6 (TLR2 dimerized with TLR6), but not TLR2/1 (TLR2 dimerized with TLR1), significantly increased IL-6 expression by U937 mononuclear cells, coactivation of TLR4 and TLR2/6, but not TLR4 and TLR2/1, led to a further augmentation on IL-6 expression by increasing IL-6 transcriptional activity, but not mRNA stability. To explore the signaling mechanisms involved in the augmentation, we found that p38 MAPK and NFκB pathways, but not ERK and JNK pathways, were required for the augmentation of IL-6 expression by coactivation of TLR4 and TLR2/6. Furthermore, we found that coactivation of TLR4 and TLR2/6 increased p38 phosphorylation, but not NFkB activity, as compared to activation of TLR4 or TLR2/6 alone. Taken together, this study showed that coactivation of TLR4 and TLR2/6 coordinates an additive augmentation of IL-6 gene transcription via p38 MAPK pathway in U937 mononuclear cells.

295 Epidermal growth factor relieves inflammatory signals in Staphylococcus aureus treated human epidermal keratinocytes and atopic dermatitis-like skin lesions in Nc/Nga mice

“…Furthermore, we confirmed that HKSA-induced TLR2 overexpression in keratinocytes is related to transcription factors, including p38, NF B, and ERK (MAPK1, MAPK3). In agreement with our study, it has been shown that TLR-2 activation induces IL-6 gene transcription through p38 and NF B signaling [17]. Previous studies have revealed that EGFR signaling restricts allergen-induced IL-6 production in an acute AD model [4], and EGFR acts as a negative regulator of TLR2 induction via p38 MAPK [18].…”

High-Mobility Group Box-1 Induces Proinflammatory Cytokines Production of Kupffer Cells through TLRs-Dependent Signaling Pathway after Burn Injury

“…HMGB1 was shown to rapidly interact with TLR2 and TLR4 exposed by RAW macrophage-like cells in one study [36], but not in the other study [29]. RAGE has been demonstrated to play only a minor role in macrophage activation by HMGB1 [15], [37]. Our previous study also showed that pre-incubation of KCs with anti-RAGE antibody and recombinant mouse RAGE/Fc chimera both failed to decrease HMGB1-induced TNF-α and IL-1β production [data not shown], implying that the majority of KCs activation by HMGB1 was independent of RAGE.…”

Intestinal Serotonin Transporter Inhibition by Toll-Like Receptor 2 Activation. A Feedback Modulation

“…A previous study has demonstrated that cAMP/PKA system inhibits SERT activity in intestinal epithelial cells by post-translational regulation [27], which may confirm the involvement of cAMP/PKA in TLR2 short-term effect. Finally, p38 MAPK pathway, which has been demonstrated to mediate TLR2 activity in different cell types [44, 45], was analyzed. The results have shown that p38 MAPK seemed to mediate TLR2/1 and TLR2/6 effect on SERT at both short and long-term treatment.…”