INDUCTION OF HUMAN SERUM AMYLOID-A IN HEP-3B CELLS BY IL-6 AND IL-1-BETA INVOLVES BOTH TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL MECHANISMS

Previous studies of murine serum amyloid A (SAA) regulation during inf lammmatory states or following exposure to macrophage-conditioned medi um have raised the possibility that both post-transcriptional and tran scriptional mechanisms participate in induction of this family of prot eins. Since IL-6 and IL-1 have been shown to induce SAA in human hepat oma cell lines, we explored the possibility that these cytokines might induce human SAA through post-transcriptional as well as transcriptio nal mechanisms. In kinetic studies, we found that continuous exposure of Hep 3B cells to either IL-6 or IL-1 beta alone caused only minimal increases in SAA mRNA and marginal increases in transcription (as meas ured by nuclear runon). In contrast, the combination of these cytokine s led to a 23-fold increase in transcription, maximal at 12 h, with co ntinuing increase in mRNA, achieving levels more than 1000-fold greate r than baseline by 72 h. This massive disparity between increases in m RNA and in transcription rate strongly supports the participation of p ost-transcriptional mechanisms in SAA induction by (IL-6 + IL-1 beta), whereas the lag between peaks of transcription and mRNA abundance ref lects a relatively slow degradation rate of SAA mRNA. As observed by o ther workers, mean size of SAA mRNA decreased progressively over the c ourse of incubation. Simultaneous kinetic studies of complement factor s B and C3, haptoglobin, and alpha-1 protease inhibitor revealed sever al different patterns of response to IL-6 and IL-1 beta.