Inflammatory bowel disease as a disorder of an imbalance between pro- and anti-inflammatory molecules and deficiency of resolution bioactive lipids

Abstract

The inflammatory process seen in inflammatory bowel disease (IBD) is due to excess production of pro-inflammatory cytokines interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNF-α), interferons (IFNs), macrophage migration inhibitory factor (MIF), HMGB1 (high mobility group B1) and possibly, a reduction in anti-inflammatory cytokines IL-10, IL-4, and transforming growth factor-β (TGF-β). These pro-inflammatory molecules lead to increased production of reactive oxygen species (ROS) including nitric oxide resulting in target tissue damage. I propose that inadequate production of inflammation resolving molecules lipoxins, resolvins, protectins, maresins and nitrolipids that suppress inflammation, ROS production, enhance wound healing and have cytoprotective properties results in inappropriate inflammation, delay in healing/repair process and so target tissue/organ damage continues in IBD. Hence, suggested therapeutic approach could include administration of stable synthetic analogues of lipoxins, resolvins, protectins, maresins and nitrolipids. This implies that measuring urine, stool and plasma levels of lipoxins, resolvins, protectins, maresins and nitrolipids may be used to detect the onset, progression and response to treatment of IBD.

Fig. 1

Scheme showing role of pro and anti-inflammatory bioactive lipids in IBD. For easy understanding only LXA₄ has been depicted in the figure. It is to be noted that resolvins, protectins, maresins and nitrolipids may follow the same pathway as that of LXA₄ from the respective precursors (EPA and DHA: eicosapentaneoic acid and docosahexaenoic acid respectively). Possible interaction among cholinergic anti-inflammatory pathway (Ach), serotonin, dopamine and LXA₄ is also depicted in the figure. There are three classes of phospholipases that control the release of AA and other PUFAs: calcium-independent PLA₂ (iPLA₂), secretory PLA₂ (sPLA₂), and cytosolic PLA₂ (cPLA₂). Each class of PLA₂ is further divided into isoenzymes for which there are 10 for mammalian sPLA₂, at least 3 for cPLA₂, and 2 for iPLA₂. During the early phase of inflammation, COX-derived PGs and lipoxygenase-derived LTs initiate exudate formation and inflammatory cell influx. TNF-α causes an immediate influx of neutrophils concomitant with PGE₂ and LTB₄ production, whereas during the phase of resolution of inflammation an increase in LXA₄ (lipoxin A₄), PGD₂ and its product 15deoxyΔ^12-14PGJ₂ formation occurs that induces resolution of inflammation with a simultaneous decrease in PGE₂ synthesis that stops neutrophil influx and enhances phagocytosis of debris. Thus, there appears to be two waves of release of AA and other PUFAs: one at the onset of inflammation that causes the synthesis and release of PGE₂ and a second at resolution for the synthesis of anti-inflammatory PGD₂, 15deoxyΔ^12-14PGJ₂, and lipoxins that are necessary for the suppression of inflammation. Thus, COX-2 enzyme has both harmful and useful actions by virtue of its ability to give rise to pro-inflammatory and anti-inflammatory PGs and LXs. Increased type VI iPLA₂ protein expression was found to be the principal isoform expressed from the onset of inflammation up to 24 h, whereas type IIa and V sPLA₂ was expressed from the beginning of 48 h till 72 h while type IV cPLA₂ was not detectable during the early phase of acute inflammation but increased progressively during resolution peaking at 72 h. This increase in type IV cPLA₂ was mirrored by a parallel increase in COX-2 expression. The increase in cPLA₂ and COX-2 occurred in parallel, suggesting a close enzymatic coupling between these two. Thus, there is a clear-cut role for different types of PLA₂ in distinct and different phases of inflammation. Selective inhibition of cPLA₂ resulted in the reduction of pro-inflammatory molecules PGE₂, LTB₄, IL-1β, and platelet-activating factor (PAF). Furthermore, inhibition of types IIa and V sPLA₂ not only decreased PAF and LXA₄ (lipoxin A₄) but also resulted in a reduction in cPLA₂ and COX-2 activities. These results suggest that sPLA₂-derived PAF and LXA₄ induce COX-2 and type IV cPLA₂. IL-1β induced cPLA₂ expression. This suggests that one of the functions of IL-1 is not only to induce inflammation but also to induce cPLA₂ expression to initiate resolution of inflammation. Synthetic glucocorticoid dexamethasone inhibited both cPLA₂ and sPLA₂ expression, whereas type IV iPLA₂ expression is refractory to its suppressive actions. Activated iPLA₂ contributes to the conversion of inactive proIL-1β to active IL-1β, which in turn induces cPLA₂ expression that is necessary for resolution of inflammation. LXs, especially LXA₄ inhibit TNF-α-induced production of ILs; promote TNF-α mRNA decay, TNF-α secretion, and leukocyte trafficking and thus attenuated inflammation. Though the proposal presented has focused mainly on LXA₄, it may be mentioned here that there could be a significant role for other anti-inflammatory bioactive lipids such as resolvins, protectins, maresins and nitrolipids in IBD. Thus, in all the places wherever LXA₄ is mentioned, it may be assumed that resolvins, protectins, maresins and nitrolipids also have an important role to play along with LXA₄