Suppression of tumorigenicity 2 is a transmembrane protein known to regulate TLR signaling. The ST2L receptors are member of the interleukin -1R/TLR Glycitein superfamily and share structural similarities with the TLRs by having the intracellular toll-interleukin 1 receptor domain. ST2 have an essential role in development of tolerance to LPS and is involved in attenuation of TLR2 signalling. Basophils and eosinophils express ST2 constitutively and monocytes and Th2 cells express ST2 upon activation. The ligand of ST2 has recently been identified as IL-33, a member of the IL-1 superfamily. Binding of IL-33 to ST2L on Th2 cells induces release of IL-4 and IL-13 by activation of NF-kB and MAP kinases. Alternate splicing of ST2L generates a soluble variant of ST2 which increase in inflammatory disorders. Both ST2L and sST2 have negative regulating effects on TLR signalling. An important biologic consequence of TLR signalling is production of chemoattractants leading to recruitment of inflammatory cells to the site of exposure. Adhesion proteins, expressed on inflammatory and vascular cells are of importance for cell migration from the circulation to the site of inflammation. Farmers have increased serum levels of soluble L-selectin and increased expression of CD11b on blood neutrophils which might be of importance for the attenuated exposure-induced cell recruitment observed in pig farmers. To further elucidate the altered innate immune responses in farmers one aim was to investigate whether the surface expression and soluble variants of pattern recognition receptors. Pig barn environment is known to contain high levels of gram + and gram2 bacterial components and both pigs and pig farmers are frequently colonized with bacteria, such as methicillin resistant Staphylococcus aureus. We aimed to focus on the surface expression of TLR2, TLR4 and its co-receptor CD14 on blood and sputum neutrophils and to measure concentration of the soluble variant of these receptors in serum and sputum. Another aim was to investigate if surface expression of proteins involved in cell migration on blood and airway neutrophils are altered in farmers compared with healthy previously unexposed controls. A further aim was to investigate the role of ST2 as a TLR regulator in farmers and controls. Therefore, sST2 was measured in serum after in vivo exposure in a pig barn and a bronchial LPS challenge, and it was explored whether blocking of the ST2 receptor influences the release of pro-inflammatory Licochalcone-C cytokines from peripheral blood cells stimulated with TLR ligands ex vivo. The present study clearly demonstrates that continuous exposure to organic material alters innate immune responses. Thus, daily exposure to high levels of pathogen-associated molecular patterns was associated with lower number of macrophages.
Several of the intracellular negative TLR regulating systems involved in tolerance to PAMPs
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