Production and release of IL-1 beta by human peripheral blood monocytes in response to diverse stimuli: possible role of "microdamage" to account for unregulated release.

Three different stimuli [lipopolysaccharide (LPS), concanavalin A (Con A), and phorbol myristate acetate (PMA)] all induced production and release of interleukin-1 beta (IL-1 beta) from human monocytes in vitro. Of the three, LPS demonstrated the greatest potency for IL-1 beta production. LPS and Con A demonstrated similar efficacy with respect to IL-1 beta release. LPS was approximately 1000 times more potent than Con A in this regard. LPS- and Con A-induced IL-1 beta release occurred within 3 h and 12-24 h, respectively. Challenge with PMA induced low levels of IL-1 beta production with a relatively large percentage released. IL-1 beta release by all three stimuli occurred at concentrations greater than or equal to those required for optimal IL-1 beta production. The amount of IL-1 beta released correlated with total IL-1 beta produced and was associated with release of lactate dehydrogenase (LDH), a cytosolic enzyme marker used to evaluate cell membrane integrity. IL-1 beta release preceded LDH release temporally. LPS and Con A had no effect on total cell protein synthesis, a measure of overt toxicity, while PMA inhibited protein synthesis in a dose-dependent fashion. LPS and Con A both induced expression of a 33- and 29-kDa precursor IL-1 beta, but only the 17-kDa form was released. These data suggest that IL-1 beta is released by a process different from regulated secretion. While PMA induces a more profound damage, LPS and Con A may stimulate release of IL-1 beta from human monocytes in vitro through induction of microdamage to the cell membrane.