The physiological role o f SAA has yet to be clearly elucidated. In order to define or discover
a role for the protein consideration o f the proteins characteristics or properties may yield
some clues. The most notable o f these properties and probably the most important when
considering function are that SAA is an acute phase protein and that it exists predominantly
as part ofHDL^.
A number o f biological properties have been discovered for SAA. It has been found to have
chemotactic properties (Badolato e ta l 1994). Recombinant human SAA (rSAA) has been
shown to induce directional migration o f monocytes and polymorphonuclear leucocytes.
When rSAA was preincubated with HDL this chemotactic property was inhibited. This
suggests that only fi*ee SAA and not the majority o f SAA,which circulates as a part o f HDL3,
is a chemoattractant. The same study also reported that rS AA regulated expression o f the
adhesion proteins CD 11 and leucocyte cell adhesion molecule 1 and that when injected
subcutaneously into mice it recruited polymorphonuclear (PMN) cells and monocytes at
the site o f injection. The same group subsequently reported evidence that recombinant human
SAA can also induce directional migration o f both sets o f cells in vitro (Xu et a l 1995).
Inhibition o f the migration o f T cells by rSAA could be achieved by pretreating the cells
with pertussis toxin indicating the involvement o f a G-protein coupled receptor. In a similar
to the previous study when mice were injected with human rSAA, T lymphocytes were
found to be recruited to the site o f injection.
There is additional evidence to that mentioned above for a role for SAA in cell adhesion.
Preciado-Patt and coworkers (1996a) investigated the possibility that SAA may bind extra
cellular matrix (ECM) components and examined the consequences o f such binding. They
extracellular matrix glycoproteins laminin and fibronectin. This appeared to be due to the
presence o f a cell adhesive motif associated with SAA. This led the group to investigate
the possibility that SAA could in some way modulate adhesion o f cells to the ECM. They
found that binding o f recombinant human SAA to components o f the ECM is temporary
but it does induce the adhesion o f resting CD4+ cells to the ECM (Preciado-Patt et al 1996b)
. Subsequently it was also found that recombinant human SAA also induces adhesion o f
mast cells to ECM or laminin. These investigation were carried out using recombinant human
SAA and not SAA complexed with HDL3 as it is predominantly found in vivo. However
SAA complexed with HDL3 as well as recombinant human SAA has been found to bind
to human neutrophils.
Phospholipase A2 (PLA2) is an acute phase protein which is involved in the release o f
arachadonic acid from membrane phospholipids. There are two types o f PLA2, a 97kDa
cytosolic form and a 14kDa secreted form. Whereas cytosolic PLA2 non-selectively cleaves
fatty acids from phospholipids, secreted PLA2 preferentially targets arachidonyl phospholipids.
It has been found that although normal or non-acute phase HDL inhibits secretory non-pancreadc
PLA2 activity, acute phase HDL (that is SAA enriched HDL) enhances the PLA2 activity
(Pruzenski e ta l ,\995. The authors o f the work related this finding to the role o f HDL in
reverse cholesterol transport speculating that SAA could modulate the flow o f lipids as
it had been reported that hepatic lipase, an enzyme with PLA2 like activity can hydrolyse
HDL phospholipids to form HDL with increased ability to deliver cholesterol to cells.
As PLA2 causes the release o f arachadonic acid which is then converted to active metabolites
via the cycloxygenase and lipoxygenase pathways then it is possible that a protein that can
enhance this enzyme could enhance the formation and hence activities o f these metabolites.
This possibity was examined by Malle and coworkers (1997) who found that human SAAl
but not by resting monocytes. The mechanism by which this occurred however was not
elucidated and so the authors were unable to confirm that modification o f PLA2 activity
was in fact involved.
SAA has also been found to inhibit oxidative bursts o f neutrophils (Linke et al, 1991).
Both SAA and acute phase sera were able to induce the oxidative burst o f neutrophils in
response to a bacterial fMLP peptide. In contrast normal and hence reduced SAA sera had
a much reduced capacity to inhibit oxidative bursts. Inhibition o f such bursts would aid
in the prevention o f tissue damage due to the release o f reactive oxygen species.
It has been found that rabbit S AA3 can induce coUagenase synthesis in rabbit synovial fibroblasts
(Mitchell et a l 1991). It was found that these cells, at a low passage number, produced
relatively high levels o f both SAA and coUagenase. Anti-SAA3 IgG was able to prevent
coUagenase synthesis by the fibroblast cells. Synthesis o f both the SAA and coUagenase
could be increased by the use o f PMA or IL-1. This led the authors to suggest that fibroblasts
may express rabbit S AA3 at sites o f inflammation or injury and that the SAA3 acts in an
autocrine fashion to increase coUagenase synthesis.
SAA has been found to displace ApoAI from HDL suggesting a possible role in reverse
cholesterol transport (Parcs and Rudell, 1985). As was mentioned previously there is an
increase in the percentage o f the total protein content o f HDL3 that is SAA, this must be
at the expense o f another protein or proteins. Apo AI is a co-factor for the enzyme LCAT
(lecithin-cholesterol acyltransferase) which converts cholesterol to cholesterol ester, converting
the HDL3 to HDL2, which is then transported back to the Uver as part o f chylomicron remnants
and intermediate density lipoprotein (IDL) for excretion in the Uver. TheHDL2 is then converted
o f cholesterol from the extra hepatic tissues. This would coincide with reported findings
o f SAA in atherosclerotic lesions in which such accumulations are seen, (see section 1.5.1.3.3)
Lindhorst and colleagues (1997) put forward the hypothesis that the role o f SAA is to remove
cholesterol liberated fi'om damaged cells at sites o f injury. This theory suggests that instead
o f impairing the transport o f cholesterol fi'om the extra hepatic tissues, SAA would actually
have the reverse effect removing extra hepatic cholesterol released from damaged cells and
returning it to the liver. It stated that SAA modulated reverse cholesterol transport in order
to target HDL to activated macrophages, which would be present at sites o f injury or
inflammation, where the SAA would be taken into the cells. Intracellular SAA influences
the balance between cholesterol and cholesterol ester towards the former which is the more
transportable form.