Down-regulation of protein kinase C in murine splenocytes: a potential mechanism for 2-acetylaminofluorene-mediated immunosuppression.

2-Acetylaminofluorene (AAF), an arylamide carcinogen, inhibited in a dose dependent manner mouse spleen cell proliferation in response to lipopolysaccharide (LPS). The objective of the present studies was to investigate the effects of AAF on protein kinase C (PKC) activation, an enzyme required for LPS-induced splenocytes proliferation. After treatment with 50 microM AAF for 18 h, PKC activity in the cytosolic fraction decreases by 50% from the control level, and splenocytes lost 30% of total PKC activity. Furthermore, as determined by the electrophoretic mobility shift assay, AAF inhibited the binding activity of the transcription factor complex, NF-KB, whose LPS-mediated induction is dependent on PKC activation in murine splenocytes. These results strongly suggest that LPS-mediated signaling in spleen cells is interrupted by AAF early in the signal transduction pathway, at a point proximal to the activation of PKC.