The p38-MSK1 Signaling Cascade Influences Cytokine Production through CREB and C/EBP Factors in Human Neutrophils

Abstract

Neutrophils influence innate and adaptative immunity by generating numerous cytokines and chemokines whose regulation largely depends on transcriptional activators such as NF-κB and C/EBP factors. In this study, we describe the critical involvement of CREB transcription factors (CREB1 and activating transcription factor-1) in this functional response as well as relevant upstream signaling components. Neutrophil stimulation with LPS or TNF led to the phosphorylation, DNA binding activity, and chemokine promoter association of CREB1 and activating transcription factor-1. These responses occurred downstream of the p38-MSK1 signaling axis, as did the phosphorylation and promoter association of another bZIP factor, C/EBPβ. Conversely, inhibition of RSK1 failed to alter the phosphorylation of either CREB1 or C/EBPβ in neutrophils. From a more functional standpoint, the inhibition of p38 MAPK or MSK1 interfered with cytokine generation in neutrophils. Likewise, overexpression of a dominant-negative CREB1 mutant (K-CREB) or of a point mutant (S133A) resulted in a decreased ability of human neutrophil-like PLB-985 cells to generate inflammatory cytokines (CXCL8, CCL3, CCL4, and TNF-α). Collectively, our data show the involvement of CREB1 in neutrophil cytokine production, the key role of its S133 residue, important upstream signaling events, and the parallel activation of another bZIP factor. These are all potential molecular targets that could be exploited in the context of several chronic inflammatory diseases that prominently feature neutrophils and their products.

Genistein Increase Intracellular Distribution of the High Motility Group Box-1 through p38 Pathway in HeLa culture cells induced by Tumor Necrosis Factor-α

“…MSK1 activation would lead to activation of CREB (cAMP Response Element Binding Protein) [37]. This is confirmed by research Gustin (2004) [38], in which TNF-α can activate CREB through p38-MSK1 pathway via TNFR-1 receptor [38].…”

Human S100A9 potentiates IL‐8 production in response to GM‐CSF or fMLP via activation of a different set of transcription factors in neutrophils

“…Several transcription factors including CREB-1, NF-jB and STATs regulate cytokine production in neutrophils [2,22,23]. A few studies reported a direct effect of MRPs on translocation of NF-jB in murine BMC, THP-1 and human prostate cancer cells [6,19,24].…”

“…Engagement of these receptors initiates an inflammatory response via the secretion of inflammatory cytokines/chemokines and the recruitment of leukocytes. Production of cytokines and chemokines is largely dependent on transcription factors such as NF-jB and CREB-1, especially in neutrophils [1,2]. Initiation of the immune response is also amplified by secretion and liberation of DamageAssociated Molecular Patterns (DAMPs) such as HMGB-1 and S100/calgranulins, which modulate many inflammatory functions [3,4].…”

Influence of functional polymorphisms in TNF-α, IL-8, and IL-10 cytokine genes on mRNA expression levels and risk of gastric cancer

“…This allows for increased transactivation potential. It remains unclear how this transcription factor may affect cytokine production; however, it has recently been reported that CREB1 is involved in the production of inflammatory mediators such as TNF-α, IL-1, and IL-8 in tumor cell lines [65]. CREB has also been found to be involved in IL-8 production in human neutrophils induced by stimulation with Trichomonas vaginalis infection [66].…”