Tetomilast suppressed production of proinflammatory cytokines from human monocytes and ameliorated chronic colitis in IL-10-deficient mice.
BACKGROUND
Tetomilast (OPC-6535) was originally developed as a compound inhibiting superoxide production in neutrophils. Although its mechanism of action is not completely understood, phosphodiesterase type 4 inhibitory function has been postulated. The therapeutic effect of PDE4 inhibitors has been reported for chronic inflammatory disorders such as chronic obstructive pulmonary diseases. In this study we aimed to examine whether tetomilast could be a novel drug for inflammatory bowel diseases by further clarifying its antiinflammatory effects.


METHODS
Cytokines from human peripheral blood mononuclear cells were measured by enzyme-linked immunosorbent assay (ELISA) and Cytokine Beads Array. The transcripts were quantified by reverse-transcriptase polymerase chain reaction (RT-PCR). Phosphorylation of transcription factors was examined by phosflow. To examine its in vivo effect, a once-daily oral dose of tetomilast was tested in murine IL-10(-/-) chronic colitis.


RESULTS
Tetomilast suppressed TNF-alpha and IL-12 but not IL-10 production from lipopolysaccharide (LPS)-stimulated human monocytes. It suppressed TNF-alpha, IFN-gamma, and IL-10 from CD4 lymphocytes. Tetomilast suppressed cytokine production at the transcriptional level but did not alter phosphorylation of p65, ERK, p38, and STAT3. HT-89, a protein kinase A inhibitor, did not abolish the effect of tetomilast, suggesting that it was independent from the classical cAMP/PKA pathway. IL-10 was not essential to the inhibitory effect of tetomilast on TNF-alpha and IL-12. Tetomilast ameliorated IL-10(-/-) chronic colitis with reduced clinical symptoms, serum amyloid A, and histological scores with decreased TNF-alpha mRNA expression.


CONCLUSIONS
Tetomilast exerts its antiinflammatory effects on human monocytes and CD4 cells. Combined with in vivo data these findings support the feasibility of tetomilast as a novel drug for inflammatory bowel diseases.
Ichikawa
Hitoshi
H
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Okamoto
Susumu
S
Kamada
Nobuhiko
N
Nagamoto
Hisashi
H
Kitazume
Mina T
MT
Kobayashi
Taku
T
Chinen
Hiroshi
H
Hisamatsu
Tadakazu
T
Hibi
Toshifumi
T
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D003092:Colitis / Q000188:drug therapy* / Q000503:physiopathology; D016207:Cytokines / Q000096:biosynthesis* / Q000187:drug effects*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016753:Interleukin-10 / Q000172:deficiency*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011336:Probability; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D013844:Thiazoles / Q000494:pharmacology*
D016207:Cytokines; D013844:Thiazoles; D016753:Interleukin-10; C108965:tetomilast