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J Rheumatol. 2004 Oct;31(10):1946-54.

Autocrine activation by interleukin 1alpha induces the fibrogenic phenotype of systemic sclerosis fibroblasts.

Author information

1
Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Abstract

OBJECTIVE:

To explore the cellular localization of interleukin 1alpha (IL-1alpha) in cultured fibroblasts from lesional skin of patients with systemic sclerosis (SSc) and to study the role of intracellular IL-1alpha in the activation of fibroblasts.

METHODS:

Dermal fibroblasts were derived from 12 patients with SSc. Expression of IL-1alpha mRNA was examined using reverse transcriptase-polymerase chain reaction (RT-PCR). The cellular distribution of IL-1alpha was examined by subcellular fractionation, flow cytometry, and immunocytochemistry. A full-length IL-1alpha cDNA was subcloned into the pcDNA3 vector to create sense and antisense-encoding constructs. Normal and SSc fibroblasts were stably transfected with the sense and antisense-encoding constructs, respectively. Stably transfected fibroblast clones were analyzed for the production of procollagen and IL-6 protein by ELISA, alpha1(I) procollagen mRNA by Northern blot hybridization, and proliferation by [3H]thymidine incorporation.

RESULTS:

SSc-affected fibroblasts constitutively expressed intracellular IL-1alpha, which was predominantly located in the nucleus. Inhibition of IL-1alpha expression in SSc-affected fibroblasts using antisense constructs resulted in decreased proliferation, IL-6 production, and procollagen synthesis. Conversely, overexpression of IL-1alpha in normal fibroblasts resulted in development of the SSc fibroblast phenotype.

CONCLUSION:

IL-1alpha is an important autocrine fibrogenic factor in SSc, suggesting that inhibition of intracellular IL-1alpha may be a novel strategy for the treatment of SSc.

PMID:
15468358
[Indexed for MEDLINE]

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