Introduction

This issue includes an interesting article by Sternberg et al. showing that the flavonoid luteolin inhibits IL-1, TNF and metalloproteinase-9 (MMP-9) release from activated peripheral blood mononuclear cells (PBMCs) from multiple sclerosis (MS) patients, and that the effect of luteolin is augmented by concurrent administration of interferon-beta (IFN-β). This paper extends previous similar results with quercetin that required higher concentrations of the flavonoid [1].

Discussion

Luteolin with or without IFN-β, could be helpful in MS by not only inhibiting PBMC release of cytokines, but also by inhibiting T cells, which we recently showed can be superstimulated by mast cells, an action also inhibited by luteolin [2]. In addition to T cells, recent evidence implicates also TH2 processes typically associated with allergic reactions [3–5], which involve mast cells (Fig. 1). In fact, mast cells have been considered as the next target for MS therapy [6–8].

Figure 1
figure 1

Diagrammatic representation of the inhibitory effect of luteolin on brain mast cells and infiltrating monocytes in the pathogenesis of multiple sclerosis.

Full size image

Brain MS plaques also contain activated mast cells [9, 10], which have been associated with brain demyelination [11–13]. Gene array analysis also showed that MS plaques had increased gene expression for the IgE receptor (FcεRI), the histamine-1 receptor and the protease tryptase, all of which are associated with mast cells [14–16]. Mast cell tryptase is elevated in the CSF of MS patients [17], can activate peripheral mononuclear cells to secrete TNF and IL-6 [18], as well as stimulate protease-activated receptors (PAR) to induce widespread inflammation [19]. Brain mast cells can secrete TNF [20], which is involved in both brain inflammation [21] and blood-brain-barrier (BBB) permeability [22]. In fact, BBB disruption precedes any pathologic signs of MS [23] and mast cells can disrupt the BBB [24, 25].

Flavonoids such as quercetin have potent anti-oxidant and anti-inflammatory activity [26]. Quercetin and luteolin also inhibit human cultured mast cell release of histamine, leukotrienes and prostaglandin D2 [27], as well as IL-6, IL-8, TNF-α and tryptase [28, 29]. Moreover, quercetin and luteolin inhibit mast cell activation stimulated by IL-1 [30] leading to selective release of IL-6. Luteolin also inhibits IL-6 release from microglia cells [31], and from astrocytes [32]. Flavonoids can also inhibit myelin phagocytosis by macrophages [33], as well as inhibit EAE [34–36].

Conclusion

Quercetin and its structurally related luteolin are safe [37]. The fact remains that less than 10% of flavonoids are absorbed orally [37]. Novel ways of delivering select flavonoid combinations would be required to assure sufficient plasma levels, especially if luteolin were to also inhibit brain inflammation. Such a test nutraceutical formulation has already been tried on a number of relapsing-remitting MS patients treated with INF-β with encouraging positive results.