Receptors
MALP-2, as so many other bacterial
products, is primarily recognized by cells of the innate immune
system, but also many other cells, through members of the
family of toll-like receptors, in this case by TLR 2 and 6.
One may visualize the TLR 2/6 heterodimer as being the active
receptor species. MALP-2 contains one center
of asymmetry in the lipid moiety. The R-stereoisomer
is the naturally occurring and biologically more active isomer.
Recognition of the synthetic S-isomer
may be facilitated by the surface molecule CD 36. Other bacterial
lipoproteins and –peptides are signaling through the TLR 1/2
heterodimer. All biological effects recorded below were achieved
with R-MALP-2,
obtained by organic synthesis and highly purified to remove
even traces of endotoxin.
Effects in cell culture
The expression of TLR 2/6 and the epigenetic potential
of the respective target cells determines their reaction to
a MALP-2 stimulus. Thus macrophages and dendritic
cells react by synthesis of proinflammatory cytokines, such
as IL-1, IL-6 and TNF, or of chemokines, such as MIP-1 and
2, MCP-1, IL-8 and RANTES. MCP-1, e.g., is also released by
MALP-2-stimulated fibroblasts. In addition,
a number of surface molecules are expressed in response to
MALP-2 by accessory cells (e.g. CD40, CD
80, CD83, CD 86), which are all important co-stimulatory molecules
for cell-cell interactions, in particular with cells of the
adaptive immune system.
In vivo effects
Also in various animal models MALP-2 exerts
pronounced effects when administered in ng to µg amounts.
Thus intraperitoneal injection causes infiltration of granulocytes
and macrophages. Instilled into the lungs MALP-2 causes
a similar reaction which is reminiscent of leukocyte infiltrations
observed on x-raying patients with M. pneumoniae infection.
Ten times higher amounts of MALP-2, when injected into
an air pouch, may cause fever and malaise. This is caused
by spillover of IL-6, formed in response to MALP-2.
IL-6 then reaches certain responsive areas of the brain by
the blood circulation. However, beneficial effects are seen
with very small amounts of locally applied MALP-2.
Thus, in full incision skin wounds of healing deficient obese
mice, submicrogram doses of MALP-2 accelerate wound
closure. In an asthma model, MALP-2 was shown to alleviate
the symptoms, an effect that is due to a T helper 2 to T helper
1 shift. In a peritonitis model MALP-2 prolonged survival,
as it did in a model of pancreas cancer (see references).
Last not least MALP-2 proved to be a very potent mucosal
adjuvant when co-administered with various antigens.
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