Therapeutic and prophylactic thalidomide in TNBS-induced colitis: Synergistic effects on TNF-α, IL-12 and VEGF production

Abstract

AIM: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 α (TNF-α), IL-12, and vascular endothelial growth factor (VEGF), hallmarks of intestinal inflammation in Crohn's 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-α 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-α and IL-12 levels were significantly reduced among TNBS induced colitis animals treated with thalidomide compared with animals that did not receive thalidomide. TNF-α levels were also significantly reduced among the animals receiving thalidomide prophylaxis compared with untreated animals with TNBS-induced colitis. Intestinal levels of TNF-α and IL-12 were significantly correlated with the inflammatory score and the number of VEGF+ cells. CONCLUSION:Thalidomide significantly attenuates TNBS-induced colitis by inhibiting the intestinal production of TNF-α, IL-12, and VEGF. This effect may support the use of thalidomide as an alternate approach in selected patients with CD.

The impact of JNK inhibitor D-JNKI-1 in a murine model of chronic colitis induced by dextran sulfate sodium

“…A comparable anti-inflammatory effect of D-JNKI-1 was previously described by our group19 in an acute form of severe TNBS colitis, which is an acute model of IBD with pathophysiological properties similar to those of Crohn’s disease 51–53. Simultaneous subcutaneous application of D-JNKI-1 significantly reduced the DAI scores.…”

Upregulation of vascular endothelial growth factor isoform VEGF-164 and receptors (VEGFR-2, Npn-1, and Npn-2) in rats with cyclophosphamide-induced cystitis

“…Intravesical corticotropinreleasing hormone and acute restraint stress induce mast celldependent VEGF release from bladder explants (7). VEGF can bind and stimulate inflammatory cells (43), and proinflammatory cytokines (e.g., IL-1␤ and TNF␣) can induce VEGF protein expression (2,8,43). In addition, bladder biopsies from IC patients with glomerulations following hydrodistension show increased expression of VEGF protein (52).…”

Corticotropin Releasing Hormone and Urocortin 3 Stimulate Vascular Endothelial Growth Factor Expression through the cAMP/CREB Pathway

“…For instance, the expression levels of VEGF-A are increased in the colonic mucosa, serum, and plasma of IBD patients compared with the healthy controls (2,3). In line with this observation, experimental mouse colitis is ameliorated by inhibition of VEGF expression and/or activity with neutralizing antibodies or thalidomide treatment (4,5). Even though emerging evidence indicates an important role of VEGF in regulating IBD, the molecular mechanism by which VEGF regulates colonic inflammation is still under investigation.…”

“…Intriguingly, it has been previously suggested that increased expression level of VEGF could promote intestinal inflammation in animal and clinical studies (2)(3)(4)(5). In light of this contention, we hypothesized that CREB Ϫ/Ϫ mice would express less VEGF than CREB ϩ/ϩ mice and thereby exhibit less severe inflammatory response than the wild type control.…”