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Title: TUMOR NECROSIS FACTOR-A (TNF-A) MODULATE INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN (IGFBPS) ACTIVITY FROM CULTURED EPITHELIAL VIA IGFBP-3 PROTEASE ACTIVITY

Author
item Elsasser, Theodore
item Caperna, Thomas
item SARTIN, J. - AUBURN UNIVERSITY
item Li, Congjun - Cj
item Kahl, Stanislaw

Submitted to: Journal of Animal Science
Publication Type: Abstract Only
Publication Acceptance Date: 7/27/2005
Publication Date: 7/27/2005
Citation: Elsasser, T.H., Sartin, J.L., Li, C., Kahl, S. 2005. Tumor necrosis factor-a decreases media content of epithelial cell-derived insulin-like growth factor binding proteins (IGFBP) in part through increased proteolytic degradation of IGFBP-3 [abstract]. Journal of Animal Science. 83(Suppl.1):209.

Interpretive Summary:

Technical Abstract: Acute proinflammatory stress is marked by significant alterations in metabolic capacity in animals mediated in part by decreased plasma and tissue levels of insulin-like growth factor-1 (IGF-1) and the respective IGFBP-2 and -3. To determine if a part of the localized tissue regulation of IGF-1 action might encompass the cellular presentation of regulatory IGFBP patterns, cultured Madin-Darby bovine kidney epithelial cells (MDBKs, ~95% confluent, 106 cells/well, 1.0 ml DMEM serum-free media) were challenged with physiologically relevant concentrations of recombinant bovine TNF-a (1 or 100 nM) in the presence and absence of the IGFBP-3 stimulator forskolin (F), a cyclic AMP pathway effector. IGFBP-2 and -3 media content was assessed by radioligand blot; IGFBP-3 protease activity was measured by adding recombinant human IGFBP-3 to media samples, incubating for 30 min and measuring the residual human IGFBP-3 by Western blot using anti-human IGFBP-3 devoid of crossreactivity with bovine IGFBP-3. Where F promoted a 50% decrease in media IGFBP-2 (P<0.02) and a 22-fold increase in media IGFBP-3 (P<0.001) content, respectively, the addition of TNF-a not only further reduced IGFBP-2 but also decreased F-stimulated IGFBP-3 media content by 70% (P<0.005). As suggested by the decrease in human IGFBP-3 band intensity, F increased media BP-3 protease activity by as much as 75%; TNF-a further increased media protease activity as evidenced by a >95% decrease in human IGFBP-3 band density. The data suggest that a significant portion of the decreased plasma and tissue IGF-1 content observed during proinflammatory stress may be associated with TNF-'-directed increases in IGFBP-3 protease activity which would have the effect of decreasing the size of the storage pool of IGF-1, namely that carried by the IGFBP-3 complex and increasing the clearance of IGF-1 from blood and tissue.