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Inhibition of interleukin‐12 expression by α ‐thrombin in human peripheral blood mononuclear cells: a potential mechanism for modulating Th1/Th2 responses
Author(s) -
Naldini A,
Aarden L,
Pucci A,
Bernini C,
Carraro F
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705514
Subject(s) - thrombin , peripheral blood mononuclear cell , coagulation , cytokine , immunology , inflammation , downregulation and upregulation , hemostasis , chemistry , microbiology and biotechnology , biology , medicine , biochemistry , platelet , in vitro , gene
In addition to its central role in blood coagulation and hemostasis, human α ‐thrombin is a powerful regulator of inflammatory responses and is known to affect cell‐mediated immunity. Interleukin (IL)‐12 is a strong promoter of the development of Th1‐type lymphocytes and its downregulation implies a positive feedback mechanism for development of Th2 responses. We have previously shown that thrombin enhances the release of IL‐6, a Th2‐related cytokine, in human peripheral blood mononuclear cells (PBMC). Here we show that thrombin downregulates IL‐12 production at both protein and mRNA levels in human PBMC. The inhibition of IL‐12 production was accompanied by an enhanced release of IL‐10, which inhibits Th1‐related processes and promotes Th2‐type responses. The use of proteolytically inactive thrombin and of the specific thrombin receptor agonist peptide, SFLLRN, reveals that this downregulation is thrombin‐specific and requires thrombin proteolytic activity. In addition, activation of coagulation inhibits IL‐12 production in whole blood cultures, confirming the tight relationship between the coagulation pathway, where thrombin is a key enzyme, and inflammation. Decreased IL‐12 production appears to be related also to IL‐10 production, since the addition of an anti‐IL‐10 monoclonal antibody to thrombin‐treated PBMC resulted in a partial restoration of IL‐12 production. In conclusion, the observation that thrombin significantly affects the production of IL‐12, as well as of IL‐10, implies a concerted role orchestrated by thrombin in PBMC that could be crucial to effective immunity and inflammation.British Journal of Pharmacology (2003) 140 , 980–986. doi: 10.1038/sj.bjp.0705514