INTERLEUKIN-1-ALPHA MEDIATES COLLAGENASE SYNTHESIS STIMULATED BY PHORBOL 12-MYRISTATE 13-ACETATE

Stimulation of collagenase expression in cultures of normal diploid fi broblasts by the tumor promotor phorbol 12-myristate 13-acetate (PMA) occurs secondarily to synthesis of unknown intermediary proteins. We h ave investigated the hypothesis that a form of the cytokine interleuki n 1 (IL-1) is one intermediate controlling PMA-stimulated collagenase expression. Treatment with an IL-1 receptor antagonist inhibits the co nstitutive synthesis of collagenase in early passage fibroblast cultur es from rabbit. Radioimmunoassay demonstrates that, of the two known I L-1 forms, IL-1alpha and IL-1beta, only IL-1alpha is synthesized and r eleased into the medium of corneal fibroblast cultures. PMA treatment of cells increases the level of IL-1alpha mRNA; this occurs prior to t he increase in collagenase mRNA and corresponds with increased synthes is and release of IL-1alpha protein. Neutralizing antiserum to EL-1alp ha inhibits constitutive collagenase synthesis. Reagents that inhibit the activity of IL-1alpha (IL-1 receptor antagonist or neutralizing an tibody) also inhibit the PMA-mediated stimulation of collagenase synth esis. These results indicate that constitutive and PMA-stimulated expr ession of collagenase is regulated through an IL-1alpha intermediate. In vivo, regulation of the lytic phase of tissue remodeling through th e IL-1alpha intermediate may ensure the recruitment of cells adjacent to the one that received the initial stimulus.