Ileal immune dysregulation in necrotizing enterocolitis: role of CD40/CD40L in the pathogenesis of disease.
OBJECTIVE
CD40, a co-stimulatory molecule, plays a critical role in coordinating enteric inflammatory immune responses. In necrotizing enterocolitis (NEC), upregulation of IL-10, a CD40-modulated cytokine, has been described, but the role of the IL-10 receptor (IL-10Rβ), CD40, and its ligand CD40L in disease pathogenesis is unknown. The study herein investigates ileal expression of CD40, CD40L, and IL-10R in a rat model of NEC.


METHODS
NEC was induced in newborn rats using established methods of formula feeding, asphyxia, and cold stress. Expression of CD40, CD40L, IL-10Rβ, and other proinflammatory molecules, including Toll-like receptor-4 (TLR-4) and IL-18, was assessed by immunoblotting. Tissue infiltration by macrophages, monocytes, and T cells was examined by confocal immunohistochemistry.


RESULTS
Ileum from rat pups with NEC showed increased expression of TLR-4, IL-18, and IL-10Rβ. Sections from both NEC and control pups demonstrated preservation of ileal cells expressing CD40/CD40L. The distal ileum of controls expressed both CD40 and CD40L; conversely, neither molecule was detected in ileal tissue from NEC pups. Additional studies showed that treatment with epidermal growth factor (EGF), previously shown to ameliorate the severity of NEC in an animal model, did not restore CD40 expression.


CONCLUSIONS
Ileal cytokine dysregulation, manifested by decreased CD40/CD40L and increased IL-10Rβ expression, may be involved in the pathogenesis of NEC. Dampened CD40 signaling may be related to enhanced IL-10 expression and a suppressed T-cell response to injury. We speculate that augmenting CD40-CD40L interactions may achieve a protective effect in this NEC model.
Division of Pediatric Gastroenterology, USA.
Jiliu
J
Xu
William R
WR
Treem
Christopher
C
Roman
Virginia
V
Anderson
Richard
R
Rubenstein
Steven M
SM
Schwarz
D000818:Animals; D015153:Blotting, Western; D019013:CD40 Antigens / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D020345:Enterocolitis, Necrotizing / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D007082:Ileum / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000276:immunology*; D053710:Interleukin-10 Receptor beta Subunit / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D023421:Models, Animal; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D019013:CD40 Antigens; C081846:IL10RB protein, human; D053710:Interleukin-10 Receptor beta Subunit; D020382:Interleukin-18; D051197:Toll-Like Receptor 4; D023201:CD40 Ligand; D004815:Epidermal Growth Factor