Laboratoire Analyse et Environnement, UMR 8587 CNRS, Université Evry Val d'Essonne, Bd. François Mitterrand, 91025 Evry CEDEX, France
Received on September 5, 2003; accepted on September 10, 2003
In this letter we want to point out that the recently published review by Berteau and Mulloy (2003) about the biological properties of fucoidan, although well documented, omits any mention of the potent inhibiting activity of this polysaccharide against the human complement system. This activity gives rise to an increasing interest, given the involvement of the complement in numerous pathological processes and the strong demand for efficient anticomplementary molecules.
The complement system is a major component of the immunity and is mainly involved in the innate and humoral response. It also allows the link between the innate immunity and the adaptive defense. An uncontrolled activation is harmful for the host organism as observed in ischemic and anaphylactic shocks or xenograft rejection (Mollnes and Fosse, 1994; Sahu and Lambris, 2000
).
The algal fucoidan from the fucale Ascophyllum nodosum has been first described as an anticomplementary molecule by Blondin et al. (1994). Since this first report, other fucoidans from fucales (Fucus evanescens) and from other brown algae of Laminariale order have been also described as inhibitors of the complement (Zvyagintseva et al., 2000
).
In an attempt to delineate the structural features of fucoidan fractions active on the complement system, a relationship between the anticomplementary activity and the molecular weight ranging from 13,500 to 40,000 g/mol was reported (Blondin et al., 1996). The sulfate groups are also essential although not a sufficient requirement to a high anticomplementary activity, as the decrease of the sulfate content from 36% to 9% did not affect the inhibition level (Blondin et al., 1996
; Zvyagintseva et al., 2000
). Compared to heparin, the fucoidan was shown to be a much more potent (up to 40-fold) inhibitor of the classical pathway, whereas both sulfated polysaccharides inhibits the alternative pathway in the same extent.
The first studies on the anticomplementary activity of fucoidan indicated that the formation of the C3 alternative and classical convertases was decreased in presence of fucoidan, but the mechanisms of this inhibitor effect remained to be established (Blondin et al., 1994). It has been recently demonstrated that A. nodosum fucoidan blocks the consumption of proteins C2 and C4, and in a less extent of protein C3 (Tissot et al., 2002
), indicating that fucoidan interferes with the first steps of the classical pathway activation. This effect is not due to the inhibition of the proteolytic activity of C1 s, the protease responsible of the activation of C2 and C4, but results from the interactions between fucoidan and the proteins C1q and C4 as demonstrated by gel coaffinity electrophoresis and affinity capillary electrophoresis, respectively. Fucoidan binding interferes with the association of the catalytic tetramer C1r2C1 s2 and C1q, responsible for the proteolytic activation of the C2 and C4 proteins, and yielding a functionally altered C1 as underscored with the observed decrease of the consumption of the proteins C2 and C4. Finally, it has been proposed that fucoidan inhibits C1 activation by binding to the collagen-like domain of C1q, likely through ionic interactions between positive residues of this domain and sulfate groups of the polysaccharide (Tissot et al., 2003
). In addition to C1q, the protein C4 and its cleavage product, C4b, are also a target for fucoidan and the affinity capillary electrophoresis used to monitor the binding of fucoidan to C4 indicated an affinity in the micromolecular range. C4b is directly involved in the formation of the classical C3 convertase, therefore its interaction with fucoidan should lead to the inhibition of the formation of the C3 convertase, thus blocking a central step in the propagation of the complement.
The capacity of fucoidan to block the formation of the classical C3 convertase may be of a great interest because it may prevent the production of the proinflammatory anaphylatoxins and of the C3b fragment. Inhibition by fucoidan at the C1q level could be also valuable to interfere with the binding to C1q receptors present on endothelial cells. Indeed the activation of the endothelial cells induced by complement is involved in graft rejection. It is worthwhile to note that fucoidan from A. nodosum has been showing promising properties in the protection of porcine endothelial cells against the complement-mediated lysis, in view of therapeutic applications for xenografts (Charreau et al., 1997).
Finally Berteau and Mulloy (2003) underlined the value of specific enzymes to obtain tailored oligosaccharides for structural and biological studies. Regarding fucoidan, the availability of sulfatases is of prime importance, and among the cited references about the fucoidan sulfatase, the authors should add the first report of a fucoidan sulfatase activity from the scallop P. maximus (Saillard et al., 1999
). This activity has been fruitfully coupled to the nonaqueous capillary electrophoresis separation of the sulfated fucose building blocks of fucoidan to identify the positional isomers (Descroix et al., 2003
).
Footnotes
1 To whom correspondence should be addressed; e-mail: regis.daniel{at}chimie.univ-evry.fr
References
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