Distinct intracellular signaling pathways control the synthesis of IL-8 and RANTES in TLR1/TLR2, TLR3 or NOD1 activated human airway epithelial cells

Inflammation is a central feature of many respiratory diseases. Airway epithelial cells are exposed to many agents present in the air that can alter their function and have important structural consequences for the airways. In this study, 19 Toll-Like Receptors (TLRs) and Nucleotide-binding Oligomerization Domain (NOD)1/NOD2 ligands were screened for their capacity to up-regulate Interleukin-8 (IL-8) and Regulated upon Activation Normal T cell Expressed and Secreted (RANTES) in airway epithelial cells. Three ligands (Pam3CSK4, Poly I:C and C12-ie-DAP) were selected for their capacity to activate different receptor complexes (TLR1/TLR2, TLR3 and NOD1 respectively) while leading to the increase of both IL-8 and RANTES albeit with distinct kinetics. Using protein kinase inhibitors we found that the Nuclear Factor κB (NFκB) pathway is essential for the transcriptional regulation of both IL-8 and RANTES following the activation of TLR1/TLR2, TLR3 and NOD1. In contrast, the Mitogen-Activated Protein Kinases (MAPKs) Extracellular signal-Regulated Kinase (ERK)1/ERK2 and p38 MAPK were necessary for the transcription of IL-8 but not RANTES. Moreover, we found that the p38 MAPK was implicated in the post-transcriptional regulation of IL-8 following TLR3 activation. The distinction made between pathways involved in the regulation of IL-8 and RANTES gives rise to the possibility of designing more targeted clinical approaches based on the biological functions to be ablated.