Down-regulation of CXCR1 and CXCR2 expression on human neutrophils upon activation of whole blood by S-aureus is mediated by TNF-alpha

It was suggested that bacterial products can inhibit the expression of leuc ocyte chemokine receptors during sepsis and affect leucocyte functions in s eptic syndrome. Superantigens and toxins produced by Staphylococcus aureus are capable of activating leucocytes via binding to MHC-II antigens on mono cytes and T-cell receptor molecules on T lymphocytes. It was recently shown that staphylococcal enterotoxins directly down-regulate the expression of CC chemokine receptors on monocytes through binding to MHC class II molecul es. We studied the effects of killed S. aureus on the expression of interle ukin-8 receptors, CXCR1 and CXCR2, on polymorphonuclear leucocytes (PMN), w hich are known to lack the expression of MHC-II antigens. It was shown that S. aureus down-regulated the cell-surface expression of CXCR1 and CXCR2 on PMN in the whole blood and total blood leucocyte fraction containing PMN a nd monocytes, but did not modulate IL-8 receptor expression in purified PMN suspension. Antibody to TNF-alpha abrogated down-regulation of IL-8 recept ors induced by S. aureus. In contrast, LPS reduced CXCR1 and CXCR2 expressi on in purified PMN and whole blood in a TNF-alpha -independent manner. We f urther showed that TNF-alpha -induced decrease of CXCR1 and CXCR2 expressio n was associated with lower IL-8 binding and lower CXCR1 and CXCR2 mRNA lev els, and was abrogated by protease inhibitors. We suggest that during septi cemia, S. aureus may inhibit neutrophil responsiveness to IL-8 and other CX C chemokines via TNF-alpha- mediated down-regulation of CXCR1 and CXCR2.