Intestinal epithelial cell-derived interleukin-7: a mechanism for the alteration of intraepithelial lymphocytes in a mouse model of total parenteral nutrition

Abstract

Total parenteral nutrition (TPN), with the absence of enteral nutrition, results in profound changes to both intestinal epithelial cells (EC) as well as the adjacent intraepithelial lymphocyte (IEL) population. Intestinal EC are a rich source of IL-7, a critical factor to support the maintenance of several lymphoid tissues, and TPN results in marked EC changes. On this basis, we hypothesized that TPN would diminish EC-derived IL-7 expression and that this would contribute to the observed changes in the IEL population. Mice received enteral food and intravenous crystalloid solution (control group) or TPN. TPN administration significantly decreased EC-derived IL-7 expression, along with significant changes in IEL phenotype; decreased IEL proliferation; and resulted in a marked decrease in IEL numbers. To better determine the relevance of TPN-related changes in IL-7, TPN mice supplemented with exogenous IL-7 or mice allowed ad libitum feeding and treated with exogenous administration of anti-IL-7 receptor (IL-7R) antibody were also studied. Exogenous IL-7 administration in TPN mice significantly attenuated TPN-associated IEL changes, whereas blocking IL-7R in normal mice resulted in several similar changes in IEL to those observed with TPN. These findings suggest that a decrease in EC-derived IL-7 expression may be a contributing mechanism to account for the observed TPN-associated IEL changes.

Glutamine Prevents Total Parenteral Nutrition-Associated Changes to Intraepithelial Lymphocyte Phenotype and Function: A Potential Mechanism for the Preservation of Epithelial Barrier Function

“…Supplementation with glutamine resulted in a return to levels not significantly different from the control group. IL-7 expression in intestinal EC was found to significantly decline with TPN, as previously reported (Yang et al , 2003c; Yang et al , 2007). Loss of IL-7 was prevented in the TPN+GLN group (Figure 1D).…”

“…TPN leads to a significant increase in IEL-derived interferon-gamma (IFN-γ) and a decline in IL-10 expression (Yang & Teitelbaum, 2003; Sun et al , 2008); and the changes in the abundance of these cytokines contribute to a loss of EBF (Yang et al , 2002a; Yang & Teitelbaum, 2003; Sun et al , 2008). Our group and others have also shown that TPN significantly decreased EC-derived IL-7 (Fukatsu et al , 2005; Yang et al , 2007); and this reduction in IL-7 may play a significant role in the alterations in the IEL (Yang et al , 2008a). …”

“…In order to understand the mechanisms which could account for the changes in IEL numbers and alteration in cytokine expression, we next investigated alterations in surface expression of IL-7 receptor (IL-7R on IEL) and CD103 (on EC); both of these being key ligands for IEL function and the ability of IEL to home to intestinal EC, respectively (Benmerah et al , 1994; Fujihashi et al , 1996; Yang et al , 2005; Yang et al , 2007). mRNA abundance showed a significant increase in IL-7R expression with TPN, and this was noted on both CD4+ and CD8+ IEL populations.…”

In Vitro Induction of Regulatory CD4+CD8α+ T Cells by TGF-β, IL-7 and IFN-γ

“…Because CD4 + CD8α + T cells represent a considerable fraction of the total CD4 + T cells within the IEL compartment, we investigated whether cytokines that are found in the epithelium may promote CD8α expression. IL-7 is expressed by human intestinal epithelial cells [11], its receptor is expressed in mucosal lymphocytes [12], and overexpression of IL-7 in intestinal epithelial cells via the villin promoter increases CD4 + CD8α + IEL numbers [13]. We therefore decided to investigate whether IL-7 promotes or enhances the expression of CD8α in in vitro activated CD4 + T cells.…”

Interleukin-7 Treatment Reverses Parenteral Nutrition-Induced Impairment of Resistance to Bacterial Pneumonia with Increased Secretory Immunoglobulin A Levels

“…Parenteral nutrition (PN) administration reportedly decreases IEC-derived IL-7 mRNA expression [5]. We have recently demonstrated intravenous injection of IL-7 to restore GALT mass even when enteral stimulation is lacking [6,7].…”