The role of interleukin-1beta and platelet-derived growth factor-AB in antifibrosis mediated by native human interferon alpha.
BACKGROUND
Commercial preparations of native human interferon alpha (nHuIFN-alpha) contain several subtypes of interferon-alpha (IFN-alpha) and traces of other cytokines. Recently, we described its antifibrotic potential and showed nHuIFN-alpha to have a greater effect than that of recombinant human IFN-alpha (rHuIFN-alpha). We hypothesized that cooperation between different cytokines in the nHuIFN-alpha preparation is essential for this effect. Considerable concentrations of interleukin-1beta (IL-1beta) and platelet-derived growth factor AB (PDGF-AB) are present in the nHuIFN-alpha preparations.


METHODS
We tested the viability and the expression of procollagen type I messenger RNA (mRNA) in MRC5 fibroblasts treated with interleukin-1 beta (IL-1beta) and/or PDGF-AB, or the corresponding antibodies in combination with rHuIFN-alpha or nHuIFN-alpha.


RESULTS
We showed that neither IL-1beta nor PDGF-AB significantly affect the viability of MRC5 cells. Furthermore, cell viability was not affected when IL-1beta or PDGF-AB were applied along with rHuIFN-alpha, relative to the viability of cells treated with rHuIFN-alpha only. In contrast, both cytokines suppressed the synthesis of procollagen type I mRNA. When coadministered with rHuIFN-alpha, IL-1beta enhanced the suppression induced by rHuIFN-alpha. Conversely, PDGF-AB acted as an antagonist of rHuIFN-alpha and restored partially the synthesis of procollagen type I mRNA. Interestingly, the addition of IL-1beta to the PDGF-AB/rHuIFN-alpha mix not only abolished the antagonistic activity of PDGF-AB but also decreased the synthesis of procollagen type I mRNA beyond the level achieved by IL-1beta/rHuIFN-alpha. Therefore, IL-1beta was able to reverse the activity of PDGF-AB.


CONCLUSIONS
Our study suggests that IL-1beta is an important component of nHuIFN-alpha preparations, acting directly and indirectly to modulate the action of other components. This study provides insight into these complex cytokine networks, which is necessary for better and safer antifibrotic therapy.
Santak
Goran
G
Department of Surgery, General County Hospital, Pozega, Croatia. gsantak@hotmail.com
Santak
Maja
M
Forcić
Dubravko
D
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics; D017931:DNA Primers; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D005355:Fibrosis / Q000517:prevention & control*; D005784:Gene Amplification; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000502:physiology*; D008168:Lung / Q000187:drug effects / Q000502:physiology; D016133:Polymerase Chain Reaction / Q000379:methods; D011347:Procollagen / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000502:physiology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use
D024042:Collagen Type I; D017931:DNA Primers; D016898:Interferon-alpha; D053583:Interleukin-1beta; D011347:Procollagen; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012313:RNA; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta