The IGF system plays critical roles in somatic growth in an endocrine fashion (somatomedin hypothesis) as well as proliferation and differentiation of normal and malignant cells in a paracrine/autocrine fashion. IGFBP-3 is known to modulate the actions of IGFs in circulation as well as the immediate extracellular environment. Interestingly, apart from the ability to inhibit or enhance IGF actions, IGFBP-3 also exhibits very clear, distinct biological effects independent of the IGF/IGF-I receptor axis. Over the past decade it has become widely appreciated that IGF/IGF-IR-independent actions of IGFBP-3 (antiproliferative and proapoptotic effects) contribute to improving the pathophysiology of a variety of human diseases, such as cancer, diabetes, and malnutrition. Recent studies have implicated interaction of IGFBP-3 with a variety of proteins or signaling cascades critical to cell cycle control and apoptosis; however, the actual mechanism of IGFBP-3 action is still unclear. This review reinforces the concept in support of the IGF/IGF-IR axis-independent actions of IGFBP-3 and delineates potential underlying mechanisms involved and subsequent biological significance, focusing in particular on functional binding partners and the clinical significance of IGFBP-3 in the assessment of cancer risk.

Insulin-like growth factor-binding protein-3 (IGFBP-3

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The dramatic effects of the anti-IgE mAb omalizumab to lower free IgE levels and FcεRI levels on basophils contrast with more modest clinical effects. Accordingly, whether IgE modulates FcεRI levels and FcεRI-dependent mediator release in vitro on human skin mast cells (MCTC type) that had matured in vivo is of interest. IgE reversibly enhanced FcεRI levels on MCTC cells in a dose- and time-dependent manner (up-regulation t1/2 of 4–5 days with 1–3 μg/ml IgE), without affecting cell proliferation. A molar ratio of omalizumab to IgE of 0.9 at baseline prevented receptor up-regulation by 50%, whereas adding omalizumab to MCTC cells already with IgE-enhanced FcεRI levels at molar ratios of 5, 12.5, and 31 reduced FcεRI levels to baseline with respective t1/2 values of 8.7, 6.3, and 4.8 days. MCTC cells with IgE-enhanced FcεRI levels were more sensitive to stimulation with a low dose of anti-FcεRI mAb in terms of degranulation and production of PGD2, GM-CSF, IL-6, IL-13, and TNF-α. Reducing up-regulated FcεRI levels with omalizumab also reduced mediator release to a low dose of anti-FcεRI mAb to baseline by 3–4 wk. Thus, reducing free IgE should decrease the hypersensitivity of allergic individuals to low naturally occurring concentrations of allergens.