Thalidomide reduces tumour necrosis factor alpha and interleukin 12 production in patients with chronic active Crohn's disease

Abstract

Background: Thalidomide improves clinical symptoms in patients with therapy refractory Crohn's disease, as shown in two recent studies. The mechanism of this effect however is still unknown. Suppression of tumour necrosis factor alpha (TNF-alpha) by thalidomide has been suggested as a possible mechanism. However, effects on other cytokines have not been adequately investigated.

Aim: The aim of our study was to investigate the effects of thalidomide on cytokine production in patients with inflammatory bowel disease (IBD).

Methods: Ten patients with therapy refractory IBD (nine Crohn's disease, one ulcerative colitis) received thalidomide 300 mg daily in a 12 week open label study. Production of TNF-alpha, interleukin (IL)-1 beta, IL-6, and IL-12 was investigated in short term cultures of stimulated colonic lamina propria mononuclear cells (LPMC) and peripheral blood monocytes (PBMC) before and after 12 weeks of treatment. LPMC were also cultured with graded doses of thalidomide.

Results: Three patients discontinued treatment because of sedative side effects. In the other patients, disease activity decreased significantly, with four patients achieving remission. Production of TNF-alpha and IL-12 decreased during treatment with thalidomide: LPMC (TNF-alpha: 42.3 (8.3) pg/ml v 16.4 (6.3); IL-12: 9.7 (3.3) v 5.0 (2.5); p<0.04) and PBMC (TNF-alpha: 62.8 (14.6) v 22.5 (9.2); p<0.02). Production of IL-1 beta and IL-6 did not change significantly. Culturing of LPMC with thalidomide showed a dose dependent decrease in TNF-alpha and IL-12 production.

Conclusion: The clinical effects of thalidomide in Crohn's disease may be mediated by reduction of both TNF-alpha and IL-12.

Figures

Figure 1

Crohn's disease activity index (CDAI) and Crohn's disease endoscopic index of severity (CDEIS) after treatment with thalidomide. CDAI scores (A) decreased from 309 (31) before treatment to 227 (63) after four weeks, 216 (56) after eight weeks, and 187 (53) after 12 weeks of treatment. CDEIS (B) also significantly decreased after treatment with thalidomide. *p

Figure 2

Production of tumour necrosis factor α (TNF-α) (A) and interleukin 12 (IL-12) (B) by pokeweed mitogen (PWM) stimulated and unstimulated lamina propria mononuclear cells (LPMC) after treatment with thalidomide (n=7). TNF-α and IL-12 production by LPMC decreased within two weeks of treatment with thalidomide. Data show cytokine production as a percentage of levels before treatment with thalidomide: TNF-α: 42.3 (8.3) pg/ml (stimulated), 17.0 (3.9) pg/ml (unstimulated); IL-12: 9.7 (3.2) pg/ml (stimulated), 7.3 (1.9) pg/ml (unstimulated). *p

Figure 3

Titration of lamina propria mononuclear cells (LPMC) with increasing doses of thalidomide. Inhibition by thalidomide of production of tumour necrosis factor α (TNF-α) and interleukin 12 (IL-12) was observed in both unstimulated (A) and pokeweed mitogen (PWM) stimulated LPMC (B) (n=8). Data show cytokine production as a percentage of control without thalidomide: TNF-α: 20.8 (5.0) pg/ml (unstimulated), 49.8 (6.9) pg/ml (stimulated); IL-12: 12.0 (2.0) pg/ml (unstimulated), 17.2 (3.3) pg/ml (stimulated). *p