The Involvement of the Apoptosis-Modulating Proteins ERK 1/2, Bcl-xL and Bax in the Resolution of Acute Inflammation in Vivo

Abstract

Inflammatory cell recruitment, activation, and apoptosis are highly regulated processes involving several checkpoints controlling the resolution of inflammation. We investigated the role of the mitogen-activated protein kinase (MAPK) signaling pathway (ie, ERK1/2) and apoptosis-regulating Bcl-2 family members (ie, Bcl-x(L) and Bax) in the resolution of a rat carrageenan-induced pleurisy model. The specific ERK1/2 inhibitor PD98059 enhanced the resolution of inflammation, whereas the MEK1/2 inhibitor U0126 had no effect and the flavonoid apigenin, a nonspecific inhibitor of ERK1/2 and COX-2, augmented inflammation. Specifically, PD98059 significantly decreased the total number of macrophages and neutrophils in the pleural cavity, mainly by increasing the rate of neutrophil apoptosis, as measured by Annexin V labeling and morphological analysis. Conversely, a specific inhibitor of proapoptotic Bax (V5) increased inflammation, indicating that by preventing apoptosis in vivo, resolution of inflammation is delayed. This was associated with a decrease in neutrophil apoptosis and an increase in macrophage and neutrophil numbers perpetuating the inflammatory response. In conclusion, this study shows that ERK1/2, Bax, and Bcl-x(L) play important functional roles in the resolution phase of the acute inflammatory response in vivo by influencing apoptosis. Importantly, these data may provide novel therapeutic targets for the treatment of inflammatory diseases.

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

“…It seems likely that the early, dramatic effects of R-roscovitine on neutrophil survival are unlikely to be due to this sub-optimal inhibition of ERK phosphorylation. We feel that the observed effect is more likely to be due to downstream effects of R-roscovitine as opposed to direct inhibition especially as even powerful inhibition of ERK phosphorylation does not induce neutrophil apoptosis [14]. We have shown that R-roscovitine induces neutrophil apoptosis and also that it can resolve animal models of inflammation [23].…”

“…We have shown that R-roscovitine induces neutrophil apoptosis and also that it can resolve animal models of inflammation [23]. Interestingly, the ERK inhibitor PD50890 was also shown to have a pro-resolution effect in carrageenan-induced pleurisy without having a direct effect on neutrophil apoptosis per se [14]. Pro-resolution effects were felt to be conferred by inhibition of inflammatory mediator-triggered ERK activation responsible for neutrophil survival.…”

“…In vivo efficacy of PD098059 has been demonstrated in a rat carrageenan-induced pleurisy model where it enhanced resolution of inflammation by promoting neutrophil apoptosis within the pleural cavity. It is likely that pro-apoptotic effects of this compound are conferred by inhibition of survival factor-induced anti-apoptotic effects as it seems to have no direct effect on constitutive neutrophil apoptosis in non-inflammatory conditions [13,14].…”

Chemical constituents and biological activities of species of Justicia: a review

“…Lignans are the major components of the active extracts of the species of Justicia, exhibiting important pharmacological properties, such as antiviral, antitumoral, anti-inflamatory, and Jiménez et al, 2001;Wang et al, 2004;Woodman et al, 2005;Woodman & Malakul, 2009 Apigenin (3) Anti-inflammatory and antitumor Wahi et al, 1974;Sawatzky et al, 2006;Cai et al, 2011 Kaempferitrin (4) Antimicrobial, antiinflammatory, regulators of macrophages, and reduce the blood glucose level J. spicigera CHCl 3 Dominguez et al, 1990;Abdel-Ghani et al, 2001;Fang et al, 2005;Cazarolli et al, 2006 Vitexin (5) Anti-inflammatory and antinociceptive Wahi et al, 1974;Sridhar et al, 2006;Gorzalczany et al, 2011 Rev. Mehta et al, 1963;Ikram & Huq, 1966;Bhalla et al, 1982;Chakravarthy et al, 1982;Jindal et al, 1988;Ismail et al, 1998;Lorenz et al, 1999;Claeson et al, 2000;Shevyakov et al, 2006;Rachana et al, 2011 Vasicinone (10) Bronchodilator J. adhatoda EtOH Amin & Mehta, 1959;Mehta et al, 1963;Ikram & Huq, 1966;Bhalla et al, 1982;Chakravarthy et al, 1982;Ismail et al, 1998;Jindal et al, 1998;Lorenz et al, 1999;Rachana et al, 2011 Allantoin (11) Anti-inflammatory and anti-ulcer Fukamiya & Lee, 1986;…”

“…The vasodilator activity of the flavonoid 2 is related to the anti-hypertensive activity of the Justicia cataractae Leonard, as shown in Table 3. Apigenin (3) has been reported to exert antiinflammatory effects such as lowering oxidative stress and forestalling the expression of several inflammatory factors (Sawatzky et al, 2006). The flavonoid vitexin (5) is a potent anti-inflammatory agent, inhibiting the 5-lipoxygenase pathway, which, together with the COX-2 pathway, is very important in producing and maintaining inflammation (Sridhar et al, 2006).…”