Therapeutic and prophylactic thalidomide in TNBS-induced colitis: synergistic effects on TNF-alpha, IL-12 and VEGF production.
OBJECTIVE
To evaluated the therapeutic and prophylactic effect of thalidomide on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Thalidomide has been reported to downregulate the expression of tumor necrosis factor alpha (TNF-alpha), IL-12, and vascular endothelial growth factor (VEGF), hallmarks of intestinal inflammation in Crohnos disease (CD).


METHODS
Male Wistar rats were divided in five groups of ten animals each. Four groups received a rectal infusion of TNBS in ethanol. The first group was sacrificed 7 d after colitis induction. The second and third groups received either thalidomide or placebo by gavage and were sacrificed at 14 d. The fourth group received thalidomide 6 h before TNBS administration, and was sacrificed 7 d after induction. The fifth group acted as the control group and colitis was not induced. Histological inflammatory scores of the colon were performed and lamina propria CD4+ T cells, macrophages, and VEGF+ cells were detected by immunohistochemistry. TNF-alpha and IL-12 were quantified in the supernatant of organ cultures by ELISA.


RESULTS
Significant reduction in the inflammatory score and in the percentage of VEGF+ cells was observed in the group treated with thalidomide compared with animals not treated with thalidomide. Both TNF-alpha and IL-12 levels were significantly reduced among TNBS induced colitis animals treated with thalidomide compared with animals that did not receive thalidomide. TNF-alpha levels were also significantly reduced among the animals receiving thalidomide prophylaxis compared with untreated animals with TNBS-induced colitis. Intestinal levels of TNF-alpha and IL-12 were significantly correlated with the inflammatory score and the number of VEGF+ cells.


CONCLUSIONS
Thalidomide significantly attenuates TNBS-induced colitis by inhibiting the intestinal production of TNF-alpha, IL-12, and VEGF. This effect may support the use of thalidomide as an alternate approach in selected patients with CD.
Carvalho
Ana Teresa
AT
Departamento de Clinica Medica, Hospital Universitario Clementino Fraga Filho, Rua Barao da Torre, 666-101, Ipanema, Rio de Janeiro, RJ, Brazil. atpugas@yahoo.com.br
Souza
Heitor
H
Carneiro
Antonio Jose
AJ
Castelo-Branco
Morgana
M
Madi
Kalil
K
Schanaider
Alberto
A
Silv
Flavia
F
Pereira Junior
Fernando Antonio
FA
Pereira
Marcia G
MG
Tortori
Claudio
C
Dines
Ilana
I
Carvalho
Jane
J
Rocha
Eduardo
E
Elia
Celeste
C
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013792:Thalidomide / Q000494:pharmacology / Q000627:therapeutic use*; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D018664:Interleukin-12; D013792:Thalidomide; D014302:Trinitrobenzenesulfonic Acid