Interleukin-1beta (IL-1beta) and IL-6 modulate insulin-like growth factor-binding protein (IGFBP) secretion in colon cancer epithelial (Caco-2) cells.

Chronic inflammation is characterised by modifications in cytokine concentrations, whereas growth is mainly dependent on the GH‐IGF axis. IGF-I bioavailability is modulated by a family of IGF-binding proteins (IGFBPs). The aim of the present study was to evaluate the interactions among interleukin-1 (IL-1), IL-6 and IGFBP secretion by intestinal cells to assess whether cytokines modulate IGFBP secretion, and in turn IGF-I and IGF-II bioavailability. The human colon carcinoma derived cell line Caco-2 was used as an in vitro model for its capacity to differentiate spontaneously. Experiments were carried out on day 4 (undifferentiated state) and day 14 (differentiated state) after plating. Carcinoembryonic antigen (CEA) was used as a marker of differentiation and increased in the conditioned media (CM) from days 4 to 14 (0·20·01 ng/ml per 10 5 cells vs 3·30·2 ng/ml per 10 5 cells, P,0·05). IGFBP-2 and IGFBP-4 secretion decreased concomitantly. Cells were stimulated with IL-1 and IL-6 at 1, 10 and 50 ng/ml, and with IL-1 and IL-6 in combination at the same dose of 1 and 10 ng/ml. IGF-I at 50 ng/ml was used as a control. Caco-2 cells expressed and secreted mainly IGFBP-2 and IGFBP-4 into the CM. On day 4, IL-1 (1 ng/ml) and IL-6 (10 and 50 ng/ml) reduced IGFBP-2 by 298%, and by 329 and 388% respectively (P,0·05). IGFBP-4 was also reduced by IL-1 at 1 and 50 ng/ml (‐144% and ‐4611% vs serum free medium (SFM) respectively, P,0·05), and IL-6 at 50 ng/ml (‐4615%, P,0·05). Both IGFBP-2 and IGFBP-4 were reduced by IL-1 and IL-6 in combination at 1 and 10 ng/ml (P,0·05). On day 14, IGFBP-2 band intensity was reduced at 10 ng/ml of IL-1 (‐2215% vs SFM, P,0·05) and at 50 ng/ml of both cytokines (‐33%8% and ‐13%13% vs baseline respectively, P,0·05). IGFBP-4 band intensity decreased with 10 and 50 ng/ml of IL-1 (‐3511% and ‐4615% vs SFM respectively) and IL-6 (‐36%10% and ‐4615% vs SFM respectively). IL-1 and IL-6 in combination at 1 and 10 ng/ml reduced both IGFBP-2 and IGFBP-4. In conclusion, IGFBP-2 and IGFBP-4 secretion in CM decreased with Caco-2 cell differentiation. IGFBP-2 and IGFBP-4 were significantly decreased by IL-1 and IL-6 treatment in both the undifferentiated and differentiated state. Furthermore, these cytokines increased cell proliferation whereas total protein content was significantly reduced only at the higher concentrations of IL-6 and IL-1. These findings suggest that interleukins modulate the IGF‐IGFBP system in Caco-2 cells in vitro.