Multifunctional effects of bradykinin on glial cells in relation to potential anti-inflammatory effects

Abstract

Kinins have been reported to be produced and act at the site of injury and inflammation. Despite many reports that they are likely to initiate a particular cascade of inflammatory events, bradykinin (BK) has anti-inflammatory effects in the brain mediated by glial cells. In the present review, we have attempted to describe the complex responses and immediate reaction of glial cells to BK. Glial cells express BK receptors and induce Ca²⁺-dependent signal cascades. Among them, production of prostaglandin E₂ (PGE₂), via B₁ receptors in primary cultured microglia, has a negative feedback effect on lipopolysaccharide (LPS)-induced release of tumor necrosis factor-α (TNF-α) via increasing intracellular cyclic adenosine monophosphate (cAMP). In addition, BK up-regulates the production of neurotrophic factors such as nerve growth factor (NGF) via B₂ receptors in astrocytes. These results suggest that BK may have anti-inflammatory and neuroprotective effects in the brain through multiple functions on glial cells. These observations may help to understand the paradox on the role of kinins in the central nervous system and may be useful for therapeutic strategy.

Introduction

Kinins including bradykinin (BK) are a family of endogenous peptides in several pathophysiological events. They are formed in plasma and tissues via the kallikrein–kinin system in response to infection, tissue trauma or inflammatory alterations, such as increase in vascular permeability, oedema formation and pain. Among kinins, BK is widely distributed not only in the periphery but also in the brain (Chao et al., 1987, Raidoo and Bhoola, 1998, Scicli et al., 1984, Walker et al., 1995). Although BK is frequently regarded as an inflammatory mediator in the brain, we showed that it hardly induces inflammatory cytokines in microglia but instead suppresses the release of the inflammatory cytokines (TFN-α and IL1-β) from microglia induced by bacterial toxin lipoplysaccharide (LPS), and that this could mediate an anti-inflammatory (neuroprotective) effect on the central nervous system (Noda et al., 2006, Noda et al., 2007). The neuroprotective role of BK against glutamate toxicity has also been reported in the retina (Yasuyoshi et al., 2000). To support this idea, it was reported that BK receptor antagonists increased mortality in an animal model of global cerebral ischemia; hence the therapeutic effect of specific bradykinin receptor antagonists on functional outcome remains unclear (Lehmberg et al., 2003).

In the brain, glial cells are considered to be the pathologic response element; both microglial cells (Kim and de Vellis, 2005, Kreutzberg, 1996, Perry et al., 1993) and astrocytes (reviewed by Takano et al., 2007). Microglial cells represent the immune system of the mammalian brain and therefore are critically involved in various injuries and diseases. On the other hand, astrocytes are the most abundant non-neuronal cells in the central nervous system, and their role in physiological and pathophysiological processes is becoming increasingly appreciated (Volterra and Meldolesi, 2005). BK receptors were reported in microglia (Noda et al., 2003) and astrocytes (Stephens et al., 1993, Gimpl et al., 1992, Hosli et al., 1992, Lin and Chuang, 1992). In astrocytes, BK induced expression of matrix metalloproteinase-9, phospholipase A2 and COX-2 (Hsieh et al., 2004, Hsieh et al., 2006, Hsieh et al., 2007) and increased expression and secretion of IL-6 (Schwaninger et al., 1999) and glutamate (Parpura et al., 1994, Liu, 2007). Taken together, BK has multiple effects on different types of cells, inducing both inflammatory and anti-inflammatory cascades.

In the previous studies, we provided evidence that BK receptors in microglia mediate anti-inflammatory or neuroprotective effects, namely the inhibition of LPS-induced release of TNF-α and IL-1β (Noda et al., 2007). In the brain, microglial cells are dispersed throughout the entire CNS and exhibit a ramified morphology under normal conditions, but their processes are highly dynamic (Davalos et al., 2005, Nimmerjahn et al., 2005) in response to mechanical stimuli or focal application of ATP, suggesting that microglial cells scan the brain parenchyma and potentially shield it from injury; their processes move rapidly toward a site of injury (for example, a damaged blood vessel in the brain) in response to the localized release of a chemoattractant such as ATP. According to their observations, microglial cells quickly extend their processes and form a barrier to protect healthy tissue (Fetler and Amigorena, 2005).

BK is also up-regulated at the site of injury and can be a candidate as one of the chemoattractants released from injured sites. In fact, BK increased the motility of microglia and attracted them as revealed by using the Boyden chamber (Ifuku et al., 2005). In many pathologic conditions, microglial cells are activated and have been reported to release immunocompetent molecules such as cytokines or chemokines, and other substances such as growth factors (Hanisch, 2002), PGE₂ and NO. However, these substances are not always toxic but sometimes neurotrophic, depending on the circumstances and their concentrations. This is why the role of microglia is called a “double-edged sword”. The problem is that little is known about the role of microglial cells in healthy brain and their immediate reaction to brain damage. It has been shown that blood–brain barrier disruption provokes immediate and focal activation of microglia, switching their behavior from patrolling to shielding of the injured site. Microglia thus are busy and vigilant housekeepers in the adult brain (Nimmerjahn et al., 2005). Though the main candidate as a chemoattractant for microglia at damaged site is ATP (Davalos et al., 2005), many other substances can also induce an immediate response of microglia. Furthermore, previous studies have shown that extracellular ATP can induce ATP release from astrocytes. ATP also mediates communication between astrocytes, and between astrocytes and microglia. Likewise, other substances released from neurons, blood vessels, astrocytes, or microglia may have multiple effects on different cell types and allow them to communicate with each other.

Here we summarize our recent results on the multiple effects of BK on glial cells and its possible neuroprotective role immediately after brain damage (as opposed to its neurotoxin role in sustained inflammation) in the central nervous system.