DIFFERENTIAL MODULATION OF PROINFLAMMATORY AND ANTIINFLAMMATORY CYTOKINE RECEPTORS BY -TRIFLUOROMETHYLPHENYL)-2-CYANO-3-HYDROXY-CROTONIC ACID AMIDE (A77-1726), THE PHYSIOLOGICALLY ACTIVE METABOLITE OF THE NOVEL IMMUNOMODULATOR LEFLUNOMIDE

(trifluoromethylphenyl)-2-cyano-3-hydroxy-crotonic acid amide (A77 172 6), the physiologically active metabolite of leflunomide, has been des cribed to exert antiproliferative effects in vitro and anti-inflammato ry actions in several animal models. Currently, its use is being evalu ated in clinical trials in psoriasis, which is characterized by epider mal hyperproliferation and infiltration of inflammatory cells. We stud ied the effects of A77 1726 on growth and gene expression in cultured epidermal cells by 5-bromo-2'-deoxy-uridine (BrdU) incorporation, reve rse transcriptase-polymerase chain reaction (RT-PCR), Northern blot hy bridizations and flow cytometry. A77 1726 inhibited epidermal prolifer ation at concentrations above 5 mu M after 24 hr. However, the cells w ere still fully viable at a concentration of 100 mu M. The drug caused a dose dependent reduction in the mRNA level of the type A receptor f or the proinflammatory cytokine interleukin-8 (IL-8-RA) and, in contra st, induced gene expression of the receptor for the anti-inflammatory cytokine IL-10 (IL-10R) at the mRNA and protein levels. In addition, t he mRNA and protein levels of the p53 gene, which is a negative cell c ycle regulator, were up-regulated by A77 1726. These data suggest that A77 1726 exerts its anti-inflammatory action via the modulation of ep idermal gene expression. (C) 1998 Elsevier Science Inc.