Differential synthesis and release of IL-18 and its antagonist, IL-18 binding protein, from human platelets (CCR4P.209)

IL-18 is a multifunctional pro-inflammatory cytokine belonging to the IL-1 family. The cytokine is known to be produced from macrophages, dendritic cells, keratinocytes, adrenal cortex etc in the human body. We found that the cytokine as well as its antagonist, IL-18 Binding Protein (IL-18BP), are produced in human platelets. Interestingly, the two of them are synthesized and released differentially from these anuclear cellular elements. Human platelets contain transcripts for the cytokine and synthesize it de novo upon activation as an inactive precursor protein, which is cleaved into mature form by activated caspase 1, whose activation occurs in activated platelets. The platelets continue to release IL-18 over several hours after activation. Freshly isolated resting platelets as well as paraformaldehyde-fixed ones contain very little IL-18. In a sharp contrast to IL-18, its antagonist (IL-18BP) is present pre-made in platelets and is released upon their activation. Platelets contain no transcripts for it and do not synthesize de novo upon activation. Freshly isolated resting platelets as well as paraformaldehyde-fixed platelets contain IL-18BP. Furthermore we found that the two soluble mediators are secreted from platelets via different mechanisms: glyburide inhibits synthesis of active IL-18 but not of IL-18BP from activated human platelets. Our findings bear important implications for a variety human diseases which are accompanied by chronic inflammation.