SHIGA TOXIN-1 REGULATION OF CYTOKINE PRODUCTION BY HUMAN PROXIMAL TUBULE CELLS

Background. Interleukin-1 (IL-1), interleukin-h (IL-6), and tumor necr osis factor (TNF) levels are elevated in kidneys of patients with post -diarrheal hemolytic uremic syndrome (D + HUS) and may contribute to r enal dysfunction. The renal cellular sources of these inflammatory cyt okines in D + HUS are largely unknown, however, the proximal tubule ha s emerged as a potentially important candidate. Since Shiga toxin-l (S tx-1) has been implicated in the genesis of D + HUS, we examined the e ffect of Stx-1 on cytokine production by human proximal tubule cells. Methods. Stx-1 cytotoxicity, protein synthesis inhibition, and effect on IL-I, IL-6, and TNF protein release and mRNA levels were determined . The effect of another protein synthesis inhibitor, cycloheximide (CH X), on these parameters was also evaluated. Results. Sts-l greatly inc reased TNF release and mRNA levels while CHX, at concentrations that p roduced similar inhibition of protein synthesis. had no effect on TNF production. In contrast, Stx-1 and CHX caused comparable elevations in IL-1 release and mRNA accumulation. Stx-1 and CHX also stimulated IL- 6 mRNA accumulation, but only at concentrations that either were cytot oxic or substantially blocked protein synthesis. Finally, lipopolysacc haride, which is likely to be elevated in the circulation of patients with D + HUS, had no effect alone, but synergized with Stx-1 to increa se IL-I production. Conclusions. These results indicate that Stx-1 sti mulates proximal tubule inflammatory cytokine production and that this effect is due partially to nonspecific induction of mRNA levels as we ll as activation of Stx-1-specific mechanisms.