Concern about the impact of fishing on ecosystems and fisheries production is increasing (1, 2). Strategies to reduce these impacts while addressing the growing need for food security (3) include increasing selectivity (1, 2): capturing species, sexes, and sizes in proportions that differ from their occurrence in the ecosystem. Increasing evidence suggests that more selective fishing neither maximizes production nor minimizes impacts (4-7). Balanced harvesting would more effectively mitigate adverse ecological effects of fishing while supporting sustainable fisheries. This strategy, which challenges present management paradigms, distributes a moderate mortality from fishing across the widest possible range of species, stocks, and sizes in an ecosystem, in proportion to their natural productivity (8), so that the relative size and species composition is maintained.

Material

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.

Neutrophils influence innate and adaptative immunity, notably through the generation of numerous cytokines and chemokines and through the modulation of their constitutive apoptosis. Several signaling cascades are known to control neutrophil responses, including the MEK pathway, which is normally coupled to ERK. However, we show here that in human neutrophils stimulated with cytokines or TLR ligands, MEK and ERK are activated independently of each other. Pharmacological blockade of MEK had no effect on the induction of ERK kinase activity and vice versa. In autologous PBMC exposed to the same stimuli or in neutrophils exposed to chemoattractants, this uncoupling of MEK and ERK was not observed. Whereas we had shown before that MEK inhibition impairs cytokine generation translationally in LPS- or TNF-stimulated neutrophils, ERK inhibition affected this response transcriptionally and translationally. Transcriptional targets or ERK include the mitogen- and stress-activated protein kinase 1 (MSK-1) and its substrates, C/EBPβ and CREB, whereas translational targets include the S6 kinase and its substrate, the S6 ribosomal protein. In addition to affecting cytokine production, ERK inhibition interfered with how LPS or TNF promotes neutrophil survival and levels of the myeloid cell leukemia 1 (Mcl-1) antiapoptotic protein. Whereas the ERK-activating kinase was not identified, we found that the MAP3K, TGF-β-activated kinase 1 (TAK1), acts upstream of ERK and MEK in neutrophils. Our results document a functional uncoupling of the MEK/ERK module under certain stimulatory conditions and suggest that therapeutic strategies based on MEK inhibition might benefit from being complemented by ERK inhibition, particularly in chronic inflammatory conditions featuring a strong neutrophilic component.