Biology Reference
In-Depth Information
TNFα release from human peripheral blood mononuclear cells
(hPBMC's) than is the parent
36
(Muller
et al.
, 1999, Moreira
et al.
,
1993) (Fig. 6.9). Agents that bind to the histamine and prostaglandin
receptors (among others) increase intracellular levels of cyclic adenosine
monophosphate (cAMP), which in turn suppresses TNFα production.
The diterpene forskolin (
39
) reversibly activates adenylate cyclase to
increase cAMP levels. Adenosine (
40
) also inhibits TNFα expression by
increasing cAMP levels after binding to the A
2
receptor (Wagner
et al.
,
1998). Phosphodiesterases (PDEs) are responsible for metabolizing
cAMP. Selective inhibition of PDE4 has shown some therapeutic
potential, since it is the major isozyme present in inflammatory cells.
Thus, the PDE4 inhibitors rolipram (
41
), nitraquazone (
42
), and
denbufylline (
43
) also inhibit TNFα generation. Unfortunately, PDE4
inhibitors such as
41
can cross the blood-brain barrier and cause nausea
in patients, since PDE4 is also present in the central nervous system. The
synthetic quinolinone vesnarinone (
44
, or OPC-8212) has been shown to
suppress TNFα production by inhibiting PDE type III in cardiac muscle
(Matsumori
et al.
, 1994).
Several classes of natural products have been reported as LPS
antagonists besides those mentioned above (Paul
et al.
, 2006). For
example, some polyphenolic flavonoid plant secondary metabolites
including some flavones, flavonols, and chalcones, are documented
TNFα secretion inhibitors (Herath
et al.
, 2003, Xagorari
et al.
, 2001).
Luteolin (
45
) and quercetin (
46
) were the most active at inhibiting TNFα
release from LPS stimulated cells (Fig. 6.10). Another plant metabolite,
scopoletin (
47
) from
Artemisia feddei
, inhibited TNFα, IL-1β, IL-6, and
prostaglandin E
2
release (Kim
et al.
, 2004). Other phenolic natural
products that have been reported to inhibit TNFα output include the
marine metabolite petrosaspongiolide M (
48
), and the phytochemicals
curcumin (
49
), 5,6-dehydrokawain (
5
0), aucubin (
51
), nardostachin (
52
),
magnosalin (
53
), and honokiol (
54
) (Chan, 1995, Hashimoto
et al.
, 2003,
Jeong
et al.
, 2002, Ju
et al.
, 2003, Ryu
et al.
, 2002, Tse
et al.
, 2005,
Posadas
et al.
, 2003). The plant alkaloid lycorine (
55
) and the diterpenes
2β,5-epoxy-5,10-dihydroxy-6α-angeloyloxy-9β-isobutyloxy-germacran-
8α,12-olide (
56
) and tanshinone II A (
57
) were all active against
TNFα induction (Yui
et al.
, 2001, Kim
et al.
, 2001, Jang
et al.
, 2003).
