Oxidative stress and 8-iso-prostaglandin F2α induce ectodomain shedding of CD163 and release of tumor necrosis factor-α from human monocytes

CD163 is a membrane glycoprotein of the cysteine-rich scavenger receptor superfamily. Upon an inflammatory stimulus CD163 undergoes ectodomain shedding and the soluble protein has been shown to play a role in downregulation of inflammation. The purpose of the present study was to identify a physiological activator of CD163 shedding that is consistently present under inflammatory conditions. Therefore, we elucidated whether oxidative stress or 8-iso-prostaglandin F2α (8-iso-PGF2α) is involved in shedding of CD163. Oxidative stress induced by H2O2 or a NO donor as well as 8-iso-PGF2α induced significant shedding of CD163. In contrast, release of CD163 was not stimulated by PGF2α. We identified both calcium and reactive oxygen species as common cellular mediators of CD163 release. Since shedding of both CD163 and tumor necrosis factor-α (TNFα) is known to be mediated by a TIMP-3-sensitive metalloproteinase we examined whether release of TNFα was induced by the same mediators that trigger shedding of CD163. Only oxidative stress generated by H2O2 as well as 8-iso-PGF2α and PGF2α enhanced TNFα secretion. Thus, we identified novel common and divergent activators of shedding of CD163 and TNFα. These inducers of shedding are present in inflammation and might play an important role in membrane protein cleavage.