Fig. 4

The production process of CXCL8 after inflammatory stimulation is tightly regulated. In response to an inflammatory trigger, pro-inflammatory cytokines like IL-1 or TNF-α induce the production of CXCL8 by stimulation of their receptors. This induces downstream signaling pathways resulting in activation of NF-κB and the AP-1 complex, which translocate into the nucleus and initiate transcription of the CXCL8 gene and production and release of CXCL8. This process is regulated at different levels. A Specific CXCL8 polymorphisms influence the CXCL8 production levels. B Transcription is only initiated after de-repression of the CXCL8 gene promoter, mediated through association of NF-κB with NF-κB-repressing factor (NRF) and the negative regulatory element (NRE) in the promoter and replacing octamer-1 (OCT-1) by the transcription factor CCAAT/enhancer-binding protein (C/EBP). This recruits the co-activator CREB-binding protein (CBP)/p300 which results in histone hyperacetylation and chromatin remodeling so that AP-1 and NF-κB can activate the gene transcription process. Anti-inflammatory stimuli like IL-10 and TGF-β can block this transcription process. C After production, the labile CXCL8 mRNA needs to be stabilized by a MAP kinase-activated protein kinase 2 (MK2)-dependent AU-rich cis-elements (ARE)-targeted mechanism through activation of the p38 MAPK pathway. This stabilization is promoted by LPS, IL-1, TNF-α, IFN-γ, nitric oxide, and hypoxia (not shown) and repressed by IL-4, IL-10, and glucocorticoids (GC) promoting mRNA degradation. D After mRNA translation, CXCL8 localizes intracellularly in the Golgi apparatus, from where it is secreted (constitutive secretory pathway). E After exocytosis, CXCL8 can be subjected to multiple post-translational modifications like proteolysis with profound effects on its activity