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Enteral Feeding Preserves Gut Th-2 Cytokines Despite Mucosal Cellular Adhesion Molecule-1 Blockade

Laurence Genton, MD, Kenneth A. Kudsk, MD^*,, Shannon R. Reese, BS and Shigeo Ikeda, MD, PhD

From the ^* Veterans Administration Surgical Services, William S. Middleton Memorial Veterans Hospital Madison, Wisconsin; and the University of Wisconsin Medical School, Department of Surgery, Madison, Wisconsin

Correspondence: Kenneth A. Kudsk, MD, University of Wisconsin Medical School, Department of Surgery, H4/730 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792-7375. Electronic mail may be sent to kudsk{at}surgery.wisc.edu.

Background: Parenteral nutrition (PN) decreases gut-associated lymphoid tissue (GALT), the intestinal IgA stimulating cytokines IL-4 and IL-10 in gut homogenates, intestinal IgA levels and the expression of Peyer patch (PP) mucosal cellular adhesion molecule-1 (MAdCAM-1), an adhesion molecule found on the high endothelial venules of PP and other tissues. IL-4 in PP stimulates MAdCAM expression in vitro. MAdCAM-1 blockade with MECA-367 reduces GALT cell populations to PN levels but maintains intestinal IgA levels if the animals are chow fed. This study compares IL-4 levels in PP of chow and PN fed mice and measures the effects of MAdCAM blockade on IL-4 and IL-10 levels in gut homogenates of chow fed mice. We hypothesized that in vivo IL-4 levels drop in PP of PN fed mice and IL-4 and IL-10 levels are maintained after MAdCAM-1 blockade in chow fed mice. Methods: Exp 1: 18 mice received chow or PN for 5 days to determine PP IL-4 levels. Exp 2: 44 mice were randomized to chow + control monoclonal antibody (mAb), chow + MECA-367 (anti-MAdCAM-1 mAb) or PN for 4 days before measurement of IL-4 and IL-10 levels in gut homogenates. Results: Exp 1: IL-4 levels in vivo were lower in PP of PN-fed mice than chow fed mice (92.0 ± 15.1 pg/mL vs 251.1 ± 14.8, p = .0003). Exp 2: IL-4 levels were significantly higher in chow + control mAb (187.1 ± 44.1 pg/mL) and chow + MECA-367 (110.9 ± 19.1 pg/mL) groups than PN mice (21.8 ± 30.6 pg/mL, p < .02 vs chow + control or chow + MECA-367). IL-10 levels were significantly lower with PN (23.1 ± 40.9 pg/mL) with chow+control (174.0 ± 22.2 pg/mL p < .01), or chow + MECA-367 (181.7 ± 23.1 pg/mL, p < .02 vs PN). Conclusions: PN-feeding reduces in vivo IL-4 levels in PP (consistent with lowered MAdCAM-1 expression) and IL-4 and IL-10 levels in gut homogenates compared with chow. Despite MAdCAM-1 blockade, enteral feeding preserved gut IL-4 levels and increased IL-10 levels consistent with preserved IgA levels.

Lack of enteral stimulation during parenteral support of nutritional status increases the risk of infectious complications, especially pneumonia and intraabdominal abscesses in critically injured patients.¹ Experimentally, at least part of this defect appears related to impaired mucosal immunity reduction in cell numbers, ² through reduction in Th-2 type IgA stimulating cytokines (IL-4 and IL-10) obtained from gut homogenates³ and isolated lamina propria cells, ⁴ and depressed IgA levels produced by the mucosal-associated lymphoid tissue.² Primary sites for sensitization of cells for intestinal and extra intestinal mucosal immunity are the Peyer patches (PP) of the small intestine. 4β7 And L-selectin on naïve T- and B-lymphocytes interact with the adhesion molecules, mucosal addressin adhesion molecule-1 (MAdCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on the vascular endothelium of the PP. This interaction initiates migration of naïve cells into the mucosal immune system.

MAdCAM-1 appears to be the most important of the PP-associated adhesion molecules because blockade of its site with an anti-MAdCAM-1 (MECA-367) monoclonal antibody (mAb) inhibits lymphocyte homing into the GALT and reduces cell numbers in the PP, lamina propria, and intraepithelial space, whereas ICAM-1 blockade does not. These histologic findings are similar to those found in mice fed parenteral nutrition (PN) with no enteral stimulation.^2,5 Surprisingly, as long as enteral stimulation with chow feeding is not interrupted, MAdCAM-1 blockade does not destroy functional mucosal immunity as PN does (ie, MAdCAM-1 does not reduce intestinal IgA levels with complete loss of antibacterial defenses).⁵ The explanation for this paradox is not clear, but we previously speculated enteral stimulation preserved intestinal Th-2 cytokine levels, despite reduction in absolute cell numbers with MECA-367. In addition, IL-4 appears to stimulate in vitro MAdCAM-1 expression in some tissues, which might explain the reduced PP MAdCAM-1 expression during PN.⁵ Although we previously measured IL-4 and IL-10 cytokines and mRNA, these measurements were in gut homogenates or isolated lamina propria cells and not in isolated PP.^3,4

The purpose of this study was to evaluate IL-4 and IL-10 levels in gut homogenates of chow-fed mice manipulated with MECA-367 and examine IL-4 levels in the PP of chow- and PN-fed mice. We hypothesized that enteral feeding preserves IL-4 and IL-10 levels despite MAdCAM blockade and that parenteral feeding reduces IL-4 levels in PP compared with chow feeding.

	MATERIALS AND METHODS

Top MATERIALS AND METHODS RESULTS DISCUSSION

 
Animals
The Animal Care and Use Committee of The University of Wisconsin–Madison approved all experimental protocols. Male ICR (Institute of Cancer Research) outbred mice were purchased from Harlan Co. (Madison, WI) and housed in an American Association for Accreditation of Laboratory Animal Care–accredited conventional facility. The environment was controlled with regard to temperature and humidity with a 12-hour light:dark cycle. Mice were fed ad libitum chow (Lab-Diet 5001; PMI International, Brentwood, MO) and water for 2 weeks before entry into protocols.

Surgical Procedure
After randomization to feeding groups, all mice were cannulated under ketamine hydrochloride (100 mg/kg body weight) and acepromazine maleate (10 mg/kg body weight) anesthesia. The proximal end of the silicone catheter (0.3 mm ID and 0.6 mm OD; Helix Medical, Carpinteria, CA) was inserted into the vena cava through the right jugular vein, whereas the distal end was run subcutaneously over the spine and exited at the midpoint of the tail. Catheterized mice were placed into metal metabolism cages with wire grid floors to eliminate coprophagia and were partially immobilized by their tail to insure catheter integrity for PN (PN) infusion. This does not seem to cause any physical or biochemical stress.⁶ After connection to infusion pumps (Instech Laboratories, Plymouth Meeting, PA), all mice received 4 mL/d of 0.9% saline IV with ad libitum chow and water for 2 days before entering the feeding protocols.

Feeding Protocols
Exp 1: effect of route of feeding on IL-4 levels in PP. Eighteen mice were randomized to chow (n = 8) or PN (n = 10). Mice given chow received 4 mL/d of 0.9% saline IV with ad libitum chow and water. Mice given PN received 4 mL of PN on the first experimental day, 6 mL on the second day, and 10 mL thereafter (1426 kJ/kg/d nonprotein energy intake, 16.1 g/kg/d protein). The PN solution contained 16% proteins, 84% dextrose (5110 kJ/L), electrolytes, and multivitamins, with a nonprotein energy-nitrogen ratio of 533 kJ/g of nitrogen.

After 5 days of experimental feedings, mice were anesthetized, weighed, and killed by cardiac puncture. All PP were excised and placed in 1 mL of lysis buffer (10 mmol/L Tris base; BioRad Laboratories, Hercules, CA; +150 mmol/L NaCl; Sigma, St. Louis, MO; adjusted to a pH of 8.0 with HCl; LabChem Inc, Pittsburgh, PA), and 1 µL of protease inhibitors (2 mmol/L phenylmethylsulfonyl fluoride and 2 µg/mL of leupeptin, pepstatin A and aprotinin; Sigma). Samples were homogenized for 30 seconds. After adding 10 µL of Triton X-100 (Sigma), homogenates were centrifuged at 15,000 rpm for 45 minutes at 4°C. IL-4 levels were measured in the supernatants using enzyme-linked immunosorbent assay (ELISA).

Exp 2: effects of MAdCAM-1 blockade on IL-4 and IL-10 levels in gut homogenates. Forty-four mice were randomized to chow + isotype control mAb (R35–95, rat IgG2_a isotypic Ab; PharMingen Inc, San Diego, CA; n = 14), chow + MECA-367 (rat IgG2_a, PharMingen Inc; n = 15) or PN (n = 14). MECA-367 and the isotype control mAb were injected IV at a loading dose of 20 µg/d on the first experimental day and 10 µg/d thereafter. MECA-367 is a specific anti-MAdCAM-1 mAb. These doses were chosen because 10 µg of MECA-367 per saturates all cell binding sites in mice, resulting in significant drops in GALT cell mass to PN levels.⁵ The TPN solution and infusion protocol were the same as in experiment 1.

After 4 experimental days, mice were anesthetized, weighed, and killed by cardiac puncture. From the proximal, middle, and distal intestine, 0.5 g of intestines were harvested and homogenized as the PP described in experiment 1 but using 2 mL of lysis buffer, 2 µL of protease inhibitors, and 20 µL of Triton X-100.³ IL-4 and IL-10 levels in the supernatants were determined by ELISA. Four days were chosen because of our observation that maximal cellular changes had occurred after 3 days.

ELISA
IL-4 and IL-10 levels in intestinal homogenates were measured by using rat antimouse IL-4 or IL-10 antibodies to coat the plates, horseradish peroxidase–conjugated goat antimouse IL-4 and IL-10 as secondary antibodies, and recombinant mouse IL-4 and IL-10 as standards (Endogen, Woburn, MA). Intestinal and nasal IgA levels were measured by coating the plates with polyclonal goat antimouse IgA and using a horseradish peroxidase–conjugated goat antimouse IgA as a secondary antibody and mouse IgA as the standard (Sigma Chemical Co).

Statistics
Statistical analysis was performed with Statview 5.0 (SAS Institute, Cary, NC, USA). Results are shown as mean ± SE. Groups were compared with analysis of variance followed, in case of significance, by Fisher's protected least significant difference post hoc test. Significance was set at p < .05.

	RESULTS

Top MATERIALS AND METHODS RESULTS DISCUSSION

 
Experiment 1
There was no significant difference in starting weights between the 2 groups. Weight loss did not differ between groups (chow: –1.3 ± 1.4 g; PN: –2.3 ± 1.9; p = .19). IL-4 levels were significantly higher in the PP after chow than after PN feeding (251.1 ± 14.8 pg/mL vs 92.0 ± 15.1 pg/mL, p = .0003).

Experiment 2
There was no difference in starting weights between the 3 groups. Weight loss was higher in PN-fed mice (–5.0 g) than in mice fed chow + isotype control mAb (–1.7 g, p < .0001) and chow + MECA367 mAb (–1.3 g, p < .0001). Chow-fed mice typically have 1.0–1.5 g of residual feces, whereas the gastrointestinal tracts of PN-fed mice are empty. IL-4 and IL-10 levels of the different feeding groups are presented in Table I. IL-4 levels in gut homogenates were significantly lower in mice fed PN than in those fed chow + isotype control mAb (p < .0001) or chow + MECA-367 mAb (p < .0001). IL-10 levels in gut homogenates were measured in 40 out of the 58 mice. Eighteen mice were excluded because the IL-10 levels were outside the range of sensitivity of the ELISA standard curve (n = 9) or because the remaining quantity of gut homogenate was insufficient to run the IL-10 ELISA test (n = 9). IL-10 levels were lower in mice fed PN than in mice fed chow + isotype control mAb (p < .0001) or chow + MECA-367 (p < .0001).

	DISCUSSION

Top MATERIALS AND METHODS RESULTS DISCUSSION

 
Parenteral feeding with no enteral stimulation (ie, gut "starvation") prevents lethal malnutrition from starvation in mice, but it generates diffuse effects upon the common mucosal immune system within days. Lack of enteral feeding reduces IgA, a basic innate, but specific, immune response within the intestine and respiratory tract. Our prior work showed that this occurs through reductions in MAdCAM-1 expression in PP, decreases in T- and B-lymphocyte numbers in the PPs and lamina propria, and drops in the Th-2 type IgA stimulating cytokines IL-4 and IL-10 in the intestine and mRNA in isolated lamina propria cells. Blockade of MAdCAM-1 induces similar cellular effects. The current work shows that PP levels drop with PN. It also demonstrates that Th-2 cytokines are maintained after MAdCAM-1 blockade despite reductions in cell populations to levels of PN-fed mice as long as enteral feeding is maintained. The work also suggests that the role of Th-2 cytokines in mucosal immunity may differ, dependent upon the site of function and local needs.

One of the early changes seen with gut "starvation" is a rapid decrease in MAdCAM-1 expression on the high endothelial venules of the PP, with no effect on MAdCAM-1 in non-PP sites.⁷ MAdCAM-1 is the primary endothelial binding adhesion molecule attracting naïve 4β7+/L-selectin+ lymphocytes into the mucosal immune system for sensitization in the PP and subsequent distribution to diffuse mucosal sites.^8–10 MAdCAM-1 in PP is modified with a carbohydrate molecule, which is especially attractive to L-selectin, a ligand strongly expressed on naïve lymphocytes. This carbohydrate molecule distinguishes it from the form found in non-PP sites, which render the molecule more attractive to 4β7. Increased expression of 4β7 occurs on lymphocytes once they are sensitized in the PP. Blockade of 4β7 or L-selectin on circulating cells or MAdCAM-1 on the PP reproduces the decrease in T- and B-cell numbers to levels of PN-fed mice. Interestingly, MAdCAM-1 blockade does not severely impair antibacterial defenses nor IgA levels,⁵ even with reduced cell numbers within the lamina propria and PP, as long as animals have access to chow. This is most likely because of the high levels of IL-4 and IL-10 relative to the number of cells present in the lamina propria. Although the levels are somewhat less than animals given the control antibody, reflecting some effect of MAdCAM-1 blockade, they are adequate to maintain effective, though slightly less vigorous, mucosal defenses and are significantly higher than PN-fed mice.

These results suggests that the role of Th-2 cytokines may differ, depending on the intestinal site of action or the form of MAdCAM-1. In the PP where MAdCAM-1 is found in the modified form, IL-4 levels were significantly depressed in PN-fed mice, supporting our hypothesis that IL-4 depression in PP might impair MAdCAM-1 expression, consistent with observed effects of IL-4 on MAdCAM-1 in some tissues.¹¹ In addition, Kerlin and Pike¹² noted an increase in the number of immunoglobulin-secreting cells in the murine PP with administration of rIL-4. We hoped this could be definitely determined by administering rIL-4 exogenously to maintain physiologic tissue levels. We embarked on experiments administering large amounts of IL-4/Fc fusion proteins designed to maintain high circulating levels of IL-4, but clearance rates were unexpectedly rapid, which failed to maintain high serum IL-4 levels. We could not document any beneficial effects upon GALT cell mass or IgA levels with the fusion protein.

Different mechanisms may be occurring in non-PP sites such as the lamina propria where cytokines may function to control IgA rather than MAdCAM-1. MAdCAM-1 in this site is unmodified and is not affected by PN or the associated decrease in Th-2 cytokines.⁷ In fact, several studies found an inverse relationship between MAdCAM-1 expression and Th-2 cytokine levels, especially IL-10 in non-PP sites. McDonald et al¹³ described decreased IL-10 transcripts in the colon and cecum of colitic IL-2 knockout mice in association with an increased number of MAdCAM-1 positive endothelial cells. Colitic IL-10 knockout mice showed higher transcripts and expression of MAdCAM-1 in the colon than wild-type mice.^14,15 IL-10 inhibits MAdCAM-1 expression¹⁶ in vivo and transfection of IL-10 expression vectors into high endothelial venules reduce MAdCAM-1 dependent lymphocyte adhesion.¹⁷ Although these studies in inflamed colonic tissue suggest an inhibitory role of the Th2 cytokine IL-10 on MAdCAM-1 expression in the colon, we were unable to detect intestinal changes in intestinal MAdCAM-1 expression despite dramatic alterations in gut and lamina propria Th-2 cytokines or their mRNA.^3,4,7

The reasons for the decrease in PP IL-4 with PN and the preservation of the cytokines with MAdCAM-1 blockade are unclear, but oral tolerance may play a role. Under physiologic conditions, enteral feeding elicits oral tolerance, a state of systemic immune hyporesponsiveness to low doses of dietary antigens. Gonella et al¹⁸ described up-regulation of IL-4, IL-10, and TGF-β in the murine GALT after low doses of ovalbumin or oligodendrocyte glycoprotein. Oral tolerance to proteins such β-lactoglobulin or ovalbumin have been associated with increased PP IL-4 production and secretion.^19,20 Thus, absence of intestinal food antigens may explain the reduced PP IL-4 and lamina propria IL-4 and IL-10 levels in PN-fed mice. Chow feeding and associated oral tolerance stimulation may be sufficient to preserve levels of Th-2 cytokines and IgA levels despite MAdCAM-1 blockade.

In summary, IL-4, a stimulant of MAdCAM-1 expression, is decreased in the PP of animals parenterally fed or known to have decreased expression of MAdCAM-1 on the high endothelial venules. With enteral feeding, MAdCAM-1 blockade using MECA-367 preserved IL-4 and IL-10 levels at normal or supernormal levels with normal IgA levels, despite cellular depletion. Physiologically, enteral feeding maintains mucosal defenses despite impairment of molecules important for cellular distribution in mucosal-associated lymphoid tissues.

Top MATERIALS AND METHODS RESULTS DISCUSSION

 
Enteral feeding overcomes reductions in mucosal immune cells caused by blockade of mucosal cellular adhesion molecule-1 (MAdCAM-1) by maintaining normal levels of Th-2 type cytokines.

Grant support: NIH grant R01 GM53439–06A1.

Received for publication August 16, 2004. Accepted for publication October 11, 2004.

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Journal of Parenteral and Enteral Nutrition, Vol. 29, No. 1, 44-47 (2005)
DOI: 10.1177/014860710502900144


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