Altered Insulin-like Growth Factor–II (IGF-II) Level and IGF-Binding Protein–3 (IGFBP-3) Protease Activity in Interstitial Fluid Taken from the Skin Lesion of Psoriasis

Abstract

In the present study, we have investigated insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) in serum and artificially raised blister fluid from uninvolved and involved areas of nine patients with psoriasis. Both levels of IGFs and IGFBP-3, and profiles of IGFBP in serum and fluid from the uninvolved areas of these patients were comparable to those seen in normal subjects. In fluid from the involved areas, the IGF-II but not IGF-I level was significantly elevated. Among five molecular forms of IGFBP, the density of 41.5- and 38.5-kDa forms of IGFBP-3 were apparently increased in fluid from the involved areas, shown by Western ligand blotting. Radioimmunoassay further showed that the IGFBP-3 concentration in the involved areas was significantly raised. Immunoblotting revealed that the predominant form of IGFBP-3 in fluid from the uninvolved areas was a 29-kDa proteolytically modified product. In contrast, intact doublet IGFBP-3 was the main form of IGFBP-3 in fluid from the involved areas. Fluid from the involved areas but not the matched serum concentration-dependently inhibited the degradation of 125I-labeled nonglycosylated IGFBP-3 (ngIGFBP-3) caused by fluid from the uninvolved areas, suggesting the presence of an IGFBP-3 protease inhibitor(s) in psoriatic skin lesion. These findings suggest that the alterations in IGF/IGFBP system may contribute to the pathogenesis of psoriasis.

Proteolysis of Insulin-Like Growth Factor-Binding Protein-3 by Human Skin Keratinocytes in Culture in Comparison to that in Skin Interstitial Fluid: The Role and Regulation of Components of the Plasmin System1

“…Thus, the protease modulates IGF availability from IGFBP-3 and, in turn, modulates the activity of this protease. In skin interstitial fluid taken from psoriatic skin lesions, the IGF-II level is significantly elevated and IGFBP-3 protease activity is greatly reduced due to a locally produced, unidentified inhibitor(s) (5). In the same fluid, the PAI-1 level was significantly higher and the PAI-2 level was lower than those in skin interstitial fluid taken from the uninvolved skin (31).…”

“…In previous studies, we have shown IGFBP-3 protease activity in skin interstitial fluid from normal skin and uninvolved skin of psoriasis, and that such activity is inhibited in involved psoriatic skin area (4,5). IGFBP messenger ribonucleic acids are present in skin epidermis (6), and keratinocytes are capable of producing IGFBPs, including IG-FBP-2, -3, -4, and -6 and possibly IGFBP-5, with IGFBP-3 being the major form (7)(8)(9).…”

Insulin-like growth factor binding proteins and mammary gland development

“…However, studies utilising more physiological conditions, perhaps involving perfusion, to simulate the kinetics of clearance in the extracellular environment, will be required to provide more compelling evidence. In this respect, comparatively little is known about tissue clearance and pericellular concentrations of IGFBPs, although there are some reports (Xu et al, 1996, Xu et al, 1997. The secretion of IGFBPs into the extracellular environment might also serve as a barrier to limit access of IGFs to cellular receptors, and such a proposal has been made for the mammary gland for IGFBP-4 (Allar and Wood, 2004) and IGFBP-5 (Flint et al, 2000).…”

Insulin-like growth factor (IGF)–binding protein-3 (IGFBP-3) proteolysis in patients with colorectal cancer: possible association with the metastatic potential of the tumor

“…However, the lack of such an inhibitor(s) in serum does not preclude that it could be produced and function out of the bloodstream, i.e., in the vicinity of a tumor by interacting with tissue-produced IGFBP-3 proteases, e.g., by tumor stromal cells. This has been reported to occur in interstitial fluid taken from psoriatic skin lesions (Xu et al, 1996). Our knowledge of where IGFBP-3 proteases are produced and how they are regulated, however, remains limited.…”