Potent inhibition of cytokine production from intestinal lamina propria T cells by phosphodiesterase-4 inhibitory thalidomide analogues.
In Crohn's disease, intestinal lamina propria (LP) T cells overproduce TNF-alpha and IFN-gamma, and clinical and animal studies indicate that this is pathogenic. Thalidomide influences cytokine production by leukocytes, inhibiting macrophage TNF-alpha, and is beneficial in treating Crohn's disease. Chemical analogues have been synthesized that may lack teratogenic and other side effects of thalidomide. We tested three analogues [selective cytokine inhibitory drugs (SelCIDs) A, B, and C, all potent PDE4 inhibitors] for effect on TNF-alpha, IFN-gamma, and IL-10 production by and on proliferation of intestinal LP mononuclear cells after T-cell stimulation and results were compared with those for peripheral blood leukocytes (PBL). While thalidomide itself had little effect, the SelCIDs were potent inhibitors, with relative inhibitory potencies: A> or =B>>C. The LP T cells were less sensitive to inhibition by the SelCIDs than were PBL. Since highly pre-activated PBL were even less sensitive, activation state alone can account for the responsiveness of intestinal LP T cells. Thalidomide analogues could play a role in treating Crohn's disease and other inflammatory disorders.
Prehn
J L
JL
Cedars-Sinai Inflammatory Bowel Disease Center, Los Angeles, California 90048, USA.
Landers
C
C
Muller
G W
GW
Man
H W
HW
Stirling
D I
DI
Targan
S R
SR
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D001485:Basement Membrane; D002455:Cell Division; D002478:Cells, Cultured; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis*; D007422:Intestines / Q000166:cytology / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D013792:Thalidomide / Q000031:analogs & derivatives*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D013792:Thalidomide; D007371:Interferon-gamma; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4