ELEVATION OF IL-6 IN TRANSGENIC MICE RESULTS IN INCREASED LEVELS OF THE 90 KDA HEAT-SHOCK-PROTEIN (HSP90) AND THE PRODUCTION OF ANTI-HSP90 ANTIBODIES

Treatment of human peripheral blood lymphocytes (PBL) in vitro with th e cytokine interleukin-6 (IL-6) induces increased levels of the 90 kDa heat shock protein (hsp90). Hsp90 levels are also elevated in PBLs of human patients with systemic lupus erythematosus (SLE) and in MRL/lpr mice with autoimmune disease. Although IL-6 is elevated in both these situations it has not been shown that it is involved in stimulating e levation of hsp90 levels in vivo. Here Ive show directly that the elev ation of IL-6 in vivo either in mice transgenic for the IL-6 gene or i n knock-out mice lacking a functional gene for the transcription facto r C/EBP beta (NF-IL-6) does indeed result in elevated hsp90 levels. Th is overexpression is associated with the specific production of autoan tibodies to hsp90 in these mice which is also observed in SLE patients and MRL/lpr mice. Hence IL-6 is likely to play a critical role in the regulation of hsp90 levels both in autoimmune disease states and pote ntially in normal cells in vivo. In turn the elevated levels of hsp90 produced in autoimmune diseases are likely to be responsible for the o bserved production of anti-hsp90 autoantibodies. (C) 1998 Academic Pre ss.