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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As an example a dendritic cell interacting with T cells is shown.
Note the long dendrites of the DC in yellow and the roundish T cells in green. DC and T cells interact with each other through the surface molecules CD 80/86 and CD 28, respectively.

(courtesy of Dr. M. Rohde, GBF)