Interleukin 1 alpha mediates collagenase synthesis stimulated by phorbol 12-myristate 13-acetate.
Stimulation of collagenase expression in cultures of normal diploid fibroblasts by the tumor promotor phorbol 12-myristate 13-acetate (PMA) occurs secondarily to synthesis of unknown intermediary proteins. We have investigated the hypothesis that a form of the cytokine interleukin 1 (IL-1) is one intermediate controlling PMA-stimulated collagenase expression. Treatment with an IL-1 receptor antagonist inhibits the constitutive synthesis of collagenase in early passage fibroblast cultures from rabbit. Radioimmunoassay demonstrates that, of the two known IL-1 forms, IL-1 alpha and IL-1 beta, only IL-1 alpha is synthesized and released into the medium of corneal fibroblast cultures. PMA treatment of cells increases the level of IL-1 alpha mRNA; this occurs prior to the increase in collagenase mRNA and corresponds with increased synthesis and release of IL-1 alpha protein. Neutralizing antiserum to IL-1 alpha inhibits constitutive collagenase synthesis. Reagents that inhibit the activity of IL-1 alpha (IL-1 receptor antagonist or neutralizing antibody) also inhibit the PMA-mediated stimulation of collagenase synthesis. These results indicate that constitutive and PMA-stimulated expression of collagenase is regulated through an IL-1 alpha intermediate. In vivo, regulation of the lytic phase of tissue remodeling through the IL-1 alpha intermediate may ensure the recruitment of cells adjacent to the one that received the initial stimulus.
Fini
M E
ME
MGH/Harvard Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown 02129.
Strissel
K J
KJ
Girard
M T
MT
Mays
J W
JW
Rinehart
W B
WB
D000125:Achilles Tendon / Q000166:cytology / Q000201:enzymology*; D000818:Animals; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis* / Q000187:drug effects / Q000302:isolation & purification; D003315:Cornea / Q000166:cytology / Q000201:enzymology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis / Q000502:physiology*; D009928:Organ Specificity; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology*; D013583:Synovial Membrane / Q000166:cytology / Q000201:enzymology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D017364:Collagenases; D013755:Tetradecanoylphorbol Acetate