The IGF system in patients with inflammatory bowel disease treated with prednisolone or infliximab: potential role of the stanniocalcin-2 / PAPP-A / IGFBP-4 axis

Abstract

Background Patients with inflammatory bowel disease (IBD) present with reduced serum insulin-like growth factor I (IGF-I). Anti-inflammatory treatment with prednisolone or infliximab ameliorates symptoms and increases circulating IGF-I, but prednisolone induces catabolism, whereas infliximab may promote protein synthesis. Recently, stanniocalcin-2 (STC2) was discovered as a novel inhibitor of the enzyme pregnancy-associated plasma protein-A (PAPP-A), which modulates IGF-I activity. PAPP-A can cleave IGF binding protein-4 (IGFBP-4), upon which IGF-I is liberated. We hypothesized that prednisolone and infliximab exert different effects on levels of STC2, PAPP-A, and IGFBP-4, thereby explaining the distinct metabolic effects of prednisolone and infliximab. Methods Thirty-eight patients with active IBD treated with either prednisolone ( n = 17) or infliximab ( n = 21) were examined before and after 7 days of treatment. Circulating levels of IGF-I, IGF-II, IGFBP-3, PAPP-A, and STC2 were measured by immunoassays. Intact IGFBP-4 and two IGFBP-4 fragments were determined by a novel immunoassay. Bioactive IGF was assessed by cell-based IGF receptor activation assay. Concentrations of IGFBP-4, PAPP-A, and STC2 on day 0 and 7 were compared to healthy control subjects. Results Following seven days of prednisolone treatment, total and bioactive IGF-I were increased ( p < 0.001 and p < 0.05, respectively). Upon infliximab treatment, total IGF-I levels were augmented (p < 0.05), yet IGF bioactivity remained unaltered. Intact IGFBP-4 and the two IGFBP-4 fragments generated upon cleavage by PAPP-A were all decreased following treatment with either prednisolone or infliximab (all p < 0.05). PAPP-A levels were only increased by infliximab ( p = 0.005), whereas the inhibitor STC2 did not respond to any of the treatments. Conclusion IGF-I and IGFBP-4 concentrations were markedly altered in patients with IBD and near-normalized with disease remission following treatment with prednisolone or infliximab. Thus, IGFBP-4 may modulate IGF bioavailability in IBD. The effect of immunosuppression did not appear to extend beyond the regulation of IGF and IGFBP-4, as neither PAPP-A nor STC2 were discernibly affected. Trial registration ClinicalTrials.gov: NCT00955123 . Date of registration: August 7, 2009 (retrospectively registered).

Local IGF Bioactivity Associates with High PAPP-A Activity in the Pericardial Cavity of Cardiovascular Disease Patients

“…However, IGF bioactivity in plasma was similar before and during surgery. Total PAPP-A in the circulation prior to operation was similar to levels reported in healthy, nonpregnant individuals (approximately 0.8-1 ng/mL) (28)(29)(30)32), whereas intraoperative plasma levels were significantly elevated by 65-fold. Unless otherwise stated, levels of IGF-I, IGF bioactivity, IGFBP-4, PAPP-A, and STC2 in plasma from the day before surgery are compared to the pericardial fluid at initiation of surgery.…”

“…EDTA-plasma levels of intact IGFBP-4 and of the two PAPP-A generated fragments, C-terminal (CT)-IGFBP-4 and N-terminal (NT)-IGFBP-4, were measured in duplicate by in-house TR-IFMAs using monoclonal antibodies and recombinant human calibrators generously provided by HyTest Ltd. (Turku, Finland). The assays were performed as previously described (12,13,28). In each fragment assay, one of the antibodies specifically recognizes the proteolytic neoepitope generated upon cleavage by PAPP-A.…”

Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer

“…The increase in PAPP-A and PAPP-A2 in tumors and tumor microenvironments may also be reflective of other pathological processes. PAPP-A is often associated with inflammatory states, and levels are up-regulated by several pro-inflammatory cytokines, with IL-1β and tumor necrosis factor (TNF)-α being invariably potent promoters ( 43 , 44 ). Aberrant immune responses are involved in cancer patients before clinical confirmation of disease, and chronic inflammation predisposes to and is involved in the onset of tumorigenesis ( 45 ).…”

A case of ulcerative colitis associated with teprotumumab treatment for thyroid eye disease

“…Although the etiology of IBD remains unknown, patients with active disease present with reduced serum levels of IGF-1. 7 , 8 This is hypothesized to be secondary to gastrointestinal dysfunction and acquired growth hormone (GH) resistance. 9 This is possibly induced by circulating inflammatory cytokines that are elevated with chronic inflammation.…”