Glucocorticoid-induced tumour necrosis factor receptor expression: a potential molecular link between steroid intake and complicated diverticulitis?
OBJECTIVE
Immunosuppression and steroid medication have been identified as risk factors for complicated sigmoid diverticulitis. The underlying molecular mechanisms have not yet been elucidated. We hypothesized that glucocorticoid-induced tumour necrosis factor receptor (GITR) and matrix metalloproteinase-9 (MMP-9) might play a role.


METHODS
GITR and MMP-9 were analysed at protein [immunohistochemistry/immunofluorescence (IF)] and messenger RNA level (real-time polymerase chain reaction) in surgical specimens with complicated and non-complicated diverticulitis (n=101). IF double staining and regression analysis were performed for both markers. GITR expression was correlated with clinical data and its usefulness as a diagnostic test was investigated.


RESULTS
High GITR expression (≥41%) was observed in the inflammatory infiltrate in complicated diverticulitis, in contrast to non-complicated diverticulitis where GITR expression was low (P<0.001). High GITR expression was significantly associated with steroid use and pulmonary diseases (both P<0.001). MMP-9 expression correlated with GITR expression (R(2) =0.7268, P<0.0001, r=0.85) as demonstrated with IF double-staining experiments. Co-labelling of GITR with CD68, but not CD15, suggested that GITR-expressing cells in diverticulitis are macrophages. GITR expression was superior to C-reactive protein (CRP), white cell count and temperature in distinguishing complicated and non-complicated diverticulitis.


CONCLUSIONS
Our results suggest that GITR expression in inflammatory cells might potentially indicate a molecular link between steroid use and complicated forms of acute sigmoid diverticulitis. Increased MMP-9 expression by GITR signalling might explain the morphological changes in the colonic wall of perforated and phlegmonous diverticulitis. Analysis of soluble GITR might be a promising strategy for future research.
Departments of General-, Visceral-, Vascular and Pediatric Surgery PathologyUniversity of Wuerzburg Hospital, Wuerzburg, Germany. rahden_b@chirurgie.uni-wuerzburg.de
B H A
BH
von Rahden
S
S
Kircher
D
D
Landmann
N
N
Schlegel
M
M
Lazariotou
C F
CF
Jurowich
C-T
CT
Germer
M
M
Grimm
D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D004239:Diverticulitis, Colonic / Q000139:chemically induced / Q000150:complications / Q000175:diagnosis / Q000378:metabolism*; D005260:Female; D005647:Fucosyltransferases / Q000378:metabolism; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D016256:Lewis X Antigen / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008875:Middle Aged; D016017:Odds Ratio; D011446:Prospective Studies; D012372:ROC Curve; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012810:Sigmoid Diseases / Q000139:chemically induced / Q000150:complications / Q000175:diagnosis / Q000378:metabolism*; D013256:Steroids / Q000009:adverse effects*; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D005647:Fucosyltransferases; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007166:Immunosuppressive Agents; D016256:Lewis X Antigen; D020780:Matrix Metalloproteinase 9; D013256:Steroids; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C491405:TNFRSF18 protein, human; C066693:FUT4 protein, human