Novel functions of intracellular IL-1ra in human dermal fibroblasts: implications in the pathogenesis of fibrosis.
Intracellular IL-1 receptor antagonist (icIL-1ra) is reportedly involved in functions independent of blocking IL-1 receptor signaling. Fibroblasts derived from the involved skin of patients with systemic sclerosis (SSc) are predominantly of the myofibroblast phenotype, with higher levels of icIL-1ra compared to normal skin fibroblasts. We examined the effect of overexpression of icIL-1ra on the phenotype and function of normal fibroblasts with respect to the expression of alpha smooth muscle actin (alpha-SMA), a specific marker for myofibroblasts, and plasminogen activator inhibitor (PAI), a protein involved in fibrogenesis and expressed at higher levels in myofibroblasts, and the production of collagenase (matrix metalloproteinase-1 (MMP-1)), the major enzyme involved in the degradation of native collagen in the skin. Normal human foreskin fibroblasts overexpressing icIL-1ra showed higher levels of alpha-SMA and PAI and had lower levels of collagenase and MMP-1 mRNA induced by inflammatory cytokines. By contrast, levels of mRNA for tissue inhibitor of metalloproteinase-1 in the transfected cells were not different from the control cells. Pretreatment of the ic-IL-1ra-transfected cells with antisense oligonucleotide directed against the mRNA of icIL-1ra restored MMP-1 expression induced by stimulation with IL-1beta. Our data indicate novel functions for icIL-1ra, which might be relevant to the genesis of fibrotic diseases such as SSc.
Kanangat
Siva
S
Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Postlethwaite
Arnold E
AE
Higgins
Gloria C
GC
Hasty
Karen A
KA
D000199:Actins / Q000378:metabolism; D020405:Dermis / Q000166:cytology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010641:Phenotype; D015849:Plasminogen Inactivators / Q000235:genetics / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012795:Sialoglycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000199:Actins; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D020319:Oligodeoxyribonucleotides, Antisense; D015849:Plasminogen Inactivators; D012795:Sialoglycoproteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D020781:Matrix Metalloproteinase 1