Respiratory symptoms are present in workers processing a great variety of seafood, including the salmon, sardine, and king crab industry. We have previously shown that salmon trypsin is able to generate DNA-binding of NF-κB and induce secretion of IL-8 from airway epithelial cells by activating PAR-2. In this study we explore if purified trypsins from king crab (Paralithodes camtschaticus) and sardine (Sardinops melanostictus) is able to induce similar effects in cell stimulation assays. Different types of seafood seem to display dissimilar irritant/allergic potencies in human airways and molecular modelling has identified divergent positions in the king crab trypsin compared to salmon trypsin that might influence upon the binding to the N-terminal end of PAR-2, which is a prerequisite for proteolytic activation of the receptor. This knowledge inspired us to investigate if we could detect differences in intracellular signalling pathways coupled to IL-8 in human airway epithelial cells (A549) following stimulation with purified king crab and sardine trypsin. Both sardine and king crab trypsin induce secretion of IL-8 from human airway epithelial cells in a concentration-dependent manner and generate DNA-binding of activated NF-κB. By the use of siRNA we can conclude that these effects are both mediated, at lest partly, through the activation of PAR-2. The king crab and sardine trypsin displays individual differences in transformation of the NF-κB signal, as high enzyme concentrations of king crab trypsin yields high levels of NF-κB that does not translate into increased secretion of IL-8 in the cell stimulation assays. The contribution of MEK/ERK, p38 and NF-κB to the secretion of IL-8 following stimulation with purified sardine and king crab trypsins were explored by the use of specificinhibitors. The results demonstrate that MEK/ERK and NF-κB are both required for purified sardine and king crab trypsin-induced secretion of IL-8 but via separate pathways. P38 was also found to contribute to the secretion of IL-8 by seemingly NF-kB-dependent processes.The data presented indicate that small structural variations in agonists may lead to differences in receptor activation and subsequent intracellular signalling.