Pharmacologic inhibition of tpl2 blocks inflammatory responses in primary human monocytes, synoviocytes, and blood.
Tumor necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine that controls the initiation and progression of inflammatory diseases such as rheumatoid arthritis. Tpl2 is a MAPKKK in the MAPK (i.e. ERK) pathway, and the Tpl2-MEK-ERK signaling pathway is activated by the pro-inflammatory mediators TNFalpha, interleukin (IL)-1beta, and bacterial endotoxin (lipopolysaccharide (LPS)). Moreover, Tpl2 is required for TNFalpha expression. Thus, pharmacologic inhibition of Tpl2 should be a valid approach to therapeutic intervention in the pathogenesis of rheumatoid arthritis and other inflammatory diseases in humans. We have developed a series of highly selective and potent Tpl2 inhibitors, and in the present study we have used these inhibitors to demonstrate that the catalytic activity of Tpl2 is required for the LPS-induced activation of MEK and ERK in primary human monocytes. These inhibitors selectively target Tpl2 in these cells, and they block LPS- and IL-1beta-induced TNFalpha production in both primary human monocytes and human blood. In rheumatoid arthritis fibroblast-like synoviocytes these inhibitors block ERK activation, cyclooxygenase-2 expression, and the production of IL-6, IL-8, and prostaglandin E(2), and the matrix metalloproteinases MMP-1 and MMP-3. Taken together, our results show that inhibition of Tpl2 in primary human cell types can decrease the production of TNFalpha and other pro-inflammatory mediators during inflammatory events, and they further support the notion that Tpl2 is an appropriate therapeutic target for rheumatoid arthritis and other human inflammatory diseases.
Hall
J Perry
JP
Department of Inflammation, Wyeth Research, Cambridge, Massachusetts, 02140. Electronic address: jphall@wyeth.com.
Kurdi
Yahya
Y
Department of Inflammation, Wyeth Research, Cambridge, Massachusetts, 02140.
Hsu
Sang
S
Department of Inflammation, Wyeth Research, Cambridge, Massachusetts, 02140.
Cuozzo
John
J
Department of Inflammation, Wyeth Research, Cambridge, Massachusetts, 02140.
Liu
Julie
J
Department of Inflammation, Wyeth Research, Cambridge, Massachusetts, 02140.
Telliez
Jean-Baptiste
JB
Department of Inflammation, Wyeth Research, Cambridge, Massachusetts, 02140.
Seidl
Katherine J
KJ
Department of Inflammation, Wyeth Research, Cambridge, Massachusetts, 02140.
Winkler
Aaron
A
Department of Inflammation, Wyeth Research, Cambridge, Massachusetts, 02140.
Hu
Yonghan
Y
Department of Chemical and Screening Sciences, Wyeth Research, Cambridge, Massachusetts, 02140.
Green
Neal
N
Department of Chemical and Screening Sciences, Wyeth Research, Cambridge, Massachusetts, 02140.
Askew
G Roger
GR
Biological Technologies, Wyeth Research, Cambridge, Massachusetts 02140.
Tam
Steve
S
Department of Chemical and Screening Sciences, Wyeth Research, Cambridge, Massachusetts, 02140.
Clark
James D
JD
Department of Inflammation, Wyeth Research, Cambridge, Massachusetts, 02140.
Lin
Lih-Ling
LL
Department of Inflammation, Wyeth Research, Cambridge, Massachusetts, 02140. Electronic address: llin@wyeth.com.
D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001769:Blood / Q000187:drug effects*; D002384:Catalysis; D015232:Dinoprostone / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D020128:Inhibitory Concentration 50; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D020935:MAP Kinase Signaling System; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D013582:Synovial Fluid / Q000187:drug effects*
D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone