SYNERGISM OF INTERLEUKIN-1 AND INTERLEUKIN-6 INDUCES SERUM AMYLOID A PRODUCTION WHILE DEPRESSING FIBRINOGEN - A QUANTITATIVE-ANALYSIS

Objective. Production of the serum amyloid A (SAA) proteins in the liv er of patients with arthritis can be increased from -1 mu g/ml to > 10 00 mu g/ml, while fibrinogen (Fg) can be increased from 2 to 9 mg/ml. The increases appear to be regulated by mediators similar to those fou nd in inflamed joints, e.g., interleukins 1 and 6 (IL-1 and IL-6, resp ectively). The sensitivity and dose response of SAA and Fg synthesis b y hepatoma cells to IL-1 and IL-6 was investigated to understand the r elationship between the inflammatory cytokines produced in inflamed jo ints and the acute phase protein response in the liver of arthritis pa tients. Methods. SAA and Fg mRNA and protein production in human Hep3B cells stimulated by human monocyte conditioned medium (CM) containing known amounts of IL-1 and IL-6, or stimulated by corresponding concen trations of recombinant IL-1 and IL-6 was analyzed by ELISA and Northe rn blot hybridization techniques. Results. Increases in SAA mRNA and p rotein were dose dependent in the presence of IL-1 and IL-6 at concent rations ranging from 0.1 and 1 ng/ml, respectively, to 10 and 100 ng/m l, respectively. In the presence of IL-1 receptor antagonist (IL-1ra), there was a 75% decrease in SAA production and > 100% increase in Fg production by cells stimulated with CM. Conclusion. Our results demons trate that the thousand fold dynamic range associated with the acute p hase SAA response requires IL-1 acting synergistically with cytokine(s ) like IL-6. Optimum conditions for apoSAA production are suboptimal f or Fg as indicated by the differential effects of IL-1ra.