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(Journal of Leukocyte Biology. 2000;68:587-592.)
© 2000 by Society for Leukocyte Biology

Kinins and kinin receptors: importance for the activation of leukocytes

Sabine Böckmann and Inge Paegelow

Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Rostock, Germany

Correspondence: Sabine Böckmann, Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Rostock, Schillingallee 70, 18055 Rostock, Germany. E-mail: pharma-toxi{at}med.uni-rostock.de


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ABSTRACT
 
In this article, we analyzed the role of kinins and kinin receptors with respect to the activation of leukocytes. In these cells, the biological effects of kinin peptides are mediated by kinin receptor subtypes B1, B2, or both, depending on species and cell type. In contrast to the other leukocytes, neutrophils contain the complete system for the synthesis and release of bioactive kinins. Consequently, very high concentrations of these peptides can be reached in the close neighborhood of the kinin receptors, in particular at the site of inflammation. Kinins are responsible for many effects in leukocytes including the release of other inflammatory mediators, such as cytokines, prostaglandins, leukotrienes, and reactive oxygen species. Obviously, the potency of kinins to stimulate leukocytes is dependent on the differentiation and especially on the activation stage of these cells. An upregulation of kinin receptors on neutrophils and macrophages appears to be involved in increasing the sensitivity of these cells to kinins at the site of inflammation.

Key Words: kinins • inflammatory cells • G protein-coupled receptor • signal transduction


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INTRODUCTION
 
The bioactive kinins are generated by the action of a family of serine proteases, the kallikreins, on protein precursors, the kininogens [1 , 2 ]. The primary products of kininogen digestion by kallikrein are bradykinen (BK) and Lys-BK (Lys-BK, kallidin). Two other proteases, the carboxypeptidases M and N, generate the peptides desArg9-BK and Lys-desArg9-BK by removing the C-terminal arginin of BK and Lys-BK, respectively. The receptor mediating the effects of BK and Lys-BK was characterized as the kinin B2 receptor, whereas desArg9-BK and Lys-desArg9-BK operate by activation of the receptor, which is classified as kinin B1 receptor subtype [3 , 4 ]. The latter can be induced by cytokines in the situation of stress, such as shock and inflammation, whereas the kinin B2 receptor is expressed constitutively in many cell types [4 , 5 ]. Most pharmacological effects of kinins, such as vasodilatation, edema, smooth muscle contraction, pain, and hyperalgesia via stimulation of C fibers, are mediated by the kinin B2 receptor. However, accumulating evidence suggests that kinin B1 receptors can amplify or substitute the kinin B2 receptor especially at chronic inflammation processes [5 6 7 ]. An important difference between the two receptor types is that the kinin B2 receptor is internalized rapidly and desensitized, whereas the kinin B1 receptor, once induced, is not [8 ]. The kinin B1 and B2 receptors are coupled primarily via the phospholipase C (PLC)-mediated pathway under involvement of rise in intracellular Ca2+ and activation of protein kinase C (PKC). Thus, the identity of second messengers is of limited value for the classification of kinin receptors. However, the observation that kinin B1 receptor-induced responses are more persistent supports the lack of the internalization of the receptor-ligand complex [9 10 11 ].

Obviously, molecular differences exist in the regulatory promoter sequence of two genes of kinin B1 and B2 receptor. During inflammation, the kinin B1 receptor can be induced by various cytokines. In contrast, the kinin B2 receptor activation is amplified by cytokines at a different level of the signal transduction pathways [7 , 12 13 14 15 16 ]. Until now, little is known about the regulation of kinin B2 receptor expression. New studies suggest that adenosine 3',5'-cyclic monophosphate (cAMP) may regulate the expression of kinin B2 receptors [17 , 18 ].


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NEUTROPHILS AND EOSINOPHILS
 
Plasma and tissue kallikrein have been localized recently in human circulating and synovial neutrophils [19 20 21 22 ]. Also, the endogenous substrates for these proteases, the low and high molecular weight kininogens, have been identified on the external surface of this type of inflammatory cells [23 , 24 ]. The kininogens bind to specific binding sites on neutrophils. In the blood vessel, the local release of kinins by this processing system may induce the diapedesis of neutrophils by opening endothelial cell junctions. Recently, it has been postulated that neutrophils may control vascular permeability by generation of kinin [25 ]. Chemoattractants initiate the migration of these cells to the site of inflammation. Compared with other chemotactic factors, BK induces only a moderate migration of human peripheral neutrophils, whereas desArg9-BK was ineffective (unpublished results). Because the migration was inhibited by the kinin B2 receptor antagonist HOE 140, obviously the BK-induced chemotaxis is mediated by the kinin B2 receptor. In contrast, in other studies, no effect of BK on the chemotaxis of human neutrophils could be detected [25 , 26 ]. This discrepancy may be a result of the different sensitivities of the methods using to test the migration. In contrast to Heimbürger and Palmblad [27 ], we could determine a BK-induced increase in intracellular calcium concentration in some preparations of human peripheral neutrophils beyond 10 µM [28 ]. In accordance with Catz and Sterin-Speziale [29 ], we observed no BK-induced production of superoxide radicals by activation of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in neutrophils from circulation. It is now accepted that a rise in intracellular calcium [Ca2+]i is an essential step in the neutrophil activation and O2-• generation [30 , 31 ]. However, the oxidase activation occurs only if a threshold [Ca2+]i of 250 nM is exceeded [31 ]. This calcium increase was not reached by BK in our investigations [28 ]. Obviously, the cause is that peripheral neutrophils have a very low number of kinin B2 receptors (818 receptors per cell) [32 , 33 ]. However, these binding sites may be upregulated at the site of inflammation. It has been demonstrated that neutrophils isolated from synovial fluid of patients with rheumatoid arthritis show an increased kinin B2 receptor density compared with peripheral cells [33 , 34 ]. The kinins themselves and the interleukin-1ß (IL-1ß) present in the inflammatory environment can be responsible for this receptor upregulation. For IL-1ß, it could be demonstrated a moderate upregulation of kinin B2 receptors on human synovial cells [35 ]. Dalemar et al. [36 ] have shown that the activation of PKA and PKC, which can also be triggered by BK itself, modulates the expression of kinin B2 receptors in human lung fibroblasts. The functional importance of the increase in kinin B2 receptor expression on neutrophils at the site of inflammation remains to be determined.

Taken together, it now appears that the kinin receptor expressed on neutrophils is the kinin B2 receptor subtype. However, first results of investigations on kinin B1 receptor knockout mice have demonstrated that the function of polymorphonuclear leukocytes is altered: The accumulation of this cell type in inflamed tissues was reduced by about 65% [37 ]. Another group has shown that kinin B1 receptors are involved in the IL-1ß-induced cellular migration of neutrophils in air pouches under the skin of mice [38 ]. This neutrophil migration in response to the cytokine was reduced by the kinin B1 receptor antagonist des-Arg9[Leu8]-BK. The kinin B2 receptor antagonist HOE 140 had no effect. However, the neutrophils accumulated at the site of IL-1ß injection did not show any response to the kinin B1 agonist desArg9-BK ex vivo [37 ]. In 1999, the same authors postulated that the kinin B1 receptors could be expressed on sensory C fibers during inflammatory processes. They have found that the desArg9-BK-induced cell accumulation was inhibited by neurokinin (NK)1 and calcitonin gene-related peptide (CGRP) receptor antagonists [6 ]. BK is known to release neurotransmitter, such as substance P and CGRP, from sensory nerve fibers. Obviously, under inflammatory conditions, desArg9-BK has the same effect. These locally released neuropeptides can influence the chemotactic response of leukocytes expressing the NK1 receptor [39 40 41 42 ]. Consequently, the kinin effect on neutrophil extravasation could be mediated indirectly and does not require the kinin receptor expression on leukocytes themselves. Moreover, Ahluwalia and Perretti [6 ] have postulated that the kinin B2 receptor mediates the acute stage and the kinin B1 receptor, the chronic stage of inflammation. The increased BK concentration at the inflammatory site (infiltrating leukocytes are source of BK for instance) could activate and downregulate the kinin B2 receptors resulting in the induction of kinin B1 receptor expression [5 , 6 ]. This hypothesis was supported by the finding that the incubation of fibroblasts with BK led to a loss of kinin B2 receptors, whereas the kinin B1 receptors were upregulated on these cells [7 ].

Until now, very few investigations about the effect of BK on eosinophils exist. Pasquale et al. [43 ] demonstrated that an intrathoracic injection of BK induced a dose-dependent increase in the number of eosinophils recovered from the rat pleural cavity after 24 h. However, BK did not induce eosinophil chemotaxis in vitro. The authors could show that the in vivo effect of BK is mediated indirectly by a messenger of the lipoxygenase pathway. In contrast, Silva et al. [44 ] have shown that BK by its interaction with the kinin B2 receptor down-regulated a lipopolysaccharide (LPS)-induced eosinophil accumulation in the pleural cavity of mice via a mechanism including prostanoids.

In summary, whether eosinophils express kinin receptors remains to be determined.


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MONOCYTES AND MACROPHAGES
 
Most investigations on neutrophils concerning the kinin-induced effects were performed with human neutrophils. In contrast, monocytes and macrophages of various sources and species have been used for the analysis of BK-evoked responses. Obviously, the cause is the limited monocyte number of peripheral blood compared with neutrophils and the heterogeneity of macrophages from different anatomical sites. Macrophages exist in distinct stages of differentiation/maturation or in different stages of activation correlating with changes in their receptor expression and functional response [45 , 46 ].

In contrast to neutrophils, macrophages can release various inflammatory mediators after kinin stimulation. For the first time, Burch and co-workers [47 , 48 ] have shown that BK and desArg9-BK induce tumor necrosis factor (TNF) and IL-1 release from the murine macrophage cell lines P388-D1 and RAW264.7. The cytokine production could be inhibited by the kinin B1 receptor antagonist desArg9[Leu8]-BK. Therefore, the authors have concluded the kinin receptor on macrophage cell lines is the B1 subtype. These findings have been supported by binding studies with [3H]desArg10-kallidin on RAW264.7 cells [49 ]. Investigations in our laboratory have shown that BK and desArg9-BK stimulate the cytokine release (IL-1, -2, -3, and -6) of mice spleen cells [50 ]. The inhibition of the BK effect by BK analogues with an antagonistic activity on the kinin B2 receptor suggests that the B2 receptor subtype is obviously expressed on macrophages and/or T cells of mice [50 , 51 ]. In comparison, we demonstrated by binding experiments with [3H]BK on guinea pig peritoneal macrophages that these cells express kinin B2 receptors coupling to PLC and calcium increase [52 ]. In most other cell types, the kinin B2 receptors are coupled preferentially to G proteins of the Gq subtype, resulting in PLC activation and a rise in intracellular-free Ca2+ concentration [53 , 54 ]. However, in guinea pig macrophages, we could show that the kinin B2 receptor-induced increase in [Ca2+]i is mediated by a pertussis toxin-sensitive G protein such as Gi subtype [55 ]. The BK-induced activation of guinea pig macrophages via the kinin B2 receptor resulted in an increase in the arachidonic acid and prostaglandin E2 (PGE2) release also [56 ]. Two other studies have shown that BK stimulates the PGE2 production of peritoneal macrophages of rats and peripheral human monocytes [57 , 58 ]. However, the receptor-subtype expression on monocytes/macrophages of these species has not been analyzed. Recent studies on human peripheral mononuclear cells have shown that human monocytes express a low number of kinin B2 binding sites [32 ]. However, we could not register any BK-induced increase in intracellular calcium in human monocytes and monocyte-derived macrophages (monocytes differentiate spontaneously to macrophages during culture for 7–10 days) [28 , 59 , 60 ]. This in vitro maturation is a good model for the analysis of mechanisms involved in macrophage differentiation. The differentiation of monocytes into macrophages is associated with functional and phenotypic changes. Compared with peripheral monocytes, we could demonstrate a BK-induced increase in intracellular calcium in the differentiated human monocytic cell line MONO MAC 6 [28 ]. To induce the differentiation, MONO MAC 6 cells have been treated with lipopolysaccharide and IL-1ß or interferon (IFN)-{gamma} in combination. The undifferentiated MONO MAC 6 cells did not react to BK [28 ]. Similar results have been shown for other G protein-coupled receptors, such as for the P2z/P2X7 nucleotide receptor in the human monocytic cell line THP-1 [61 ]. For the first time, Raidoo et al. [62 ] have demonstrated an intense immunolabeling for the kinin B1 receptor and a low expression of kinin B2 receptors on human foamy macrophages within the thickened intima of plaques in blood vessels of patients with atheromatous disease. The high expression of the kinin B1 receptor subtype on macrophages in this region suggests that the receptors can be induced by inflammatory mediators released during atheromatous disease.

Recently, we showed that BK can stimulate the superoxide radical generation from guinea pig macrophages via the kinin B2 receptor [55 ]. Obviously, the activation of the NADPH oxidase is associated with the BK-induced tyrosine phosphorylation of several proteins in these cells [63 ]. The secretory responses of macrophages to BK were dependent on its stage of cellular activation [55 ]. Moreover, the kinin receptor activity of resident tissue macrophages of the alveoli compared with elicited peritoneal macrophages of guinea pig was very low [55 ]. These findings have been supported by the findings that BK increased the generation of (IL-8) from alveolar macrophages of patients with active interstitial lung diseases. BK had no effect on the cells in normal human volunteers [64 ]. Further studies have demonstrated that BK as well as the kinin B1 receptor agonist stimulate bovine alveolar macrophages to release neutrophil, monocyte, and eosinophil chemotactic activity, which was identified mainly as leukotriene B4 (LTB4) [64 ]. The BK-evoked response could be inhibited by kinin B1 receptor antagonist desArg9[Leu8]-BK and kinin B2 receptor antagonist D-Arg-[Hyp3Thi5,8,D-Phe7]-BK. Obviously, both receptor subtypes were involved in BK-induced activation of bovine alveolar macrophages [64 ]. In contrast, in the rat microglia, only the kinin B2receptor subtype is expressed [65 ]. These cells are considered to be the resident macrophages of the brain, which show macrophage-like activity after activation associated with the release of cytotoxic substances such as cytokines, nitric oxide (NO), and free radicals. Walker et al. [66 ] have postulated a role of BK in the transformation of the resting microglia into an active state. Perhaps, this is an important mechanism of the neurodegeneration. Activated macrophages themselves are a source of cytokines such as IL-1ß, which may induce an autocrine mechanism of activation correlating with an increase in expression of relevant receptors. In guinea pig macrophages we could show that IL-1ß amplified the signaling and functional response to BK [16 ]. However, this effect was not associated with an increase in the kinin B2 receptor number. In contrast, in the murine alveolar macrophage cell line MH-S, IL-1ß induced the kinin B1 receptor mRNA and the receptor protein expression [12 ]. This increase in receptor number correlated with an enhancement of the desArg10-kallidin-evoked rise in intracellular calcium mobilization and TNF-{alpha} release.

Taken together, the kinin B1 receptor is expressed constitutively in some types of macrophages; in others, this receptor expression is upregulated under the influence of inflammatory mediators. Because the permanent murine alveolar macrophage cell line MH-S does not express the kinin B1 receptor constitutively, the constitutive expression of kinin B1 receptors in permanent cell lines (murine macrophages, P388-D1, and RAW264.7) cannot depend only on cytokine-rich serum containing medium or proliferative and transformed phenotypes of the cells [12 ]. Perhaps, the different origin of macrophages of these murine cell lines is responsible for the different kinin B1 receptor expression. For instance, investigations on endothelial cells of different origins and different species have shown that the kinin B1 receptor expression (constitutive or induced) and its pharmacology are dependent on cell type [67 ]. Moreover, the availability of new kinin B1 receptor antagonists, such as AcLys-desArg9[D-ßNal7,Ile8]BK (R 715) and Lys-Lys-desArg9[Hyp3, Cpg5, D-Tic7, Cpg8]BK (B 9958), has facilitated the characterization and classification of kinin B1 receptor in the mouse as a subtype of kinin B1 receptor that differs from the human and rabbit kinin B1 receptor [68 ]. The mouse kinin B1 receptor has a significantly lower affinity for both antagonists than the human and rabbit kinin B1 receptors [68 ]. Based on this pharmacological difference of the mouse kinin B1 receptor resulting obviously from minor alterations in the primary structure, a difference exists also of possible gene regulation of this receptor depending on species [69 ].

The kinin B2 receptor is expressed constitutively alone or in coexistence with the kinin B1 receptor on all macrophages of various tissue and species investigated (Table 1 ). The finding that guinea pig macrophages expressed only the kinin B2 receptor type supports many pharmacological studies in tissues of guinea pigs indicating that no kinin B1receptors are expressed in this species [70 , 71 ]. In conclusion, the results show that kinin receptor subtypes B1 and B2 are expressed on macrophages depending on species, tissue, and differentiation/activation stage (Table 1) . Obviously, the functional importance of kinin receptors on macrophages is a maintenance of the inflammatory process by release of various mediators, such as IL-1ß, which can amplify the effect of BK and metabolite desArg9-BK.


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  		Table 1. Difference in kinin receptor expression on various macrophages


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LYMPHOCYTES
 
Until now, few investigations exist about the effect of kinins and kinin receptor expression on lymphocytes. In 1979, Kimura et al. [72 ] had shown a stimulatory influence of BK on cAMP levels of murine lymphocytes. In 1982, an enhanced migration of thymocytes and T cells derived from different species had been shown after incubation with BK [73 ]. The first study, which characterized the BK receptor expressed on T lymphocytes as a B1 subtype, came from McFadden and Vickers [74 ]. They found that BK, kallidin, and desArg9-BK stimulated the migration of nonsensitized human peripheral blood and rat splenic lymphocytes. Whereas the specific kinin B1 receptor antagonist desArg9[Leu8]-BK inhibited the effect of BK and desArg9-BK, the specific kinin B2 receptor antagonists [D-Phe7]-BK and [Thi5,8, D-Phe7]-BK were ineffective [74 ]. These results were of potential interest. However, various methodological limitations (purity of cell preparation and subtyping of lymphocytes) should be controlled and confirmed by genetic experiments. A secretion of lymphokines—obviously IL-2—from T cells by BK and similar oligopeptides was demonstrated also [75 ]. In contrast to all results shown, no evidence exists that B lymphocytes react to kinins. Recently, the influence of kinins on human peripheral blood T lymphocytes of patients with multiple sclerosis (MS) compared with cells from healthy control subjects was investigated [13 ]. The authors have demonstrated an upregulation of kinin B1 receptor mRNA and protein expression on CD3+ T lymphocytes of diseased patients, especially patients with active MS compared with healthy volunteers as control. Their results indicate that the expression of kinin B1 receptor in these cells during MS correlated with the clinical activity of the disease. The in vitro finding that the cytokines TNF-{alpha} and IFN-{gamma} induced the expression of the kinin B1 receptor in CD3+ T cells of healthy control subjects supports the functional importance of this kinin-receptor subtype during the inflammatory process [13 ]. Furthermore, T cells of MS patients had an increased migration rate compared with control subjects. The kinin B1 receptor stimulation of these T lymphocytes resulted in inhibition of T cell migration. The antimigratory effect of the B1 agonist Sar(D-Phe8)desArg9BK could be prevented by the new kinin B1 antagonist R-715 [13 ]. These results provide the evidence that T lymphocytes of MS patients express functional kinin B1 receptors [13 ]. To summarize all published results of this chapter, it appears that the only expressed kinin receptor on T lymphocytes is the B1 subtype.


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CONCLUSION
 
Taken together, the results demonstrate that kinins play an important role for the activation, especially the cytokine production, of various leukocytes during the inflammatory process. The recent availability and use of potent and selective kinin receptor antagonists in different experiments provided information about which kinin receptor subtype is expressed on granulocytes, macrophages, and T lymphocytes. It is now documented that the kinin B2 receptor on neutrophils is involved in the extravascular migration of these cells at the site of inflammation. The neutrophils are participated in elevated local release of BK into inflamed tissue. Macrophages express kinin B2 as well as B1 receptors or both together. The stimulation of both receptors on macrophages results in the generation of various inflammatory mediators, such as cytokines. T lymphocytes express only the kinin B1 subtype, which can be induced by cytokines and is important for the altered migration of these cells during inflammation. This leukocyte-specific kinin receptor expression supports the hypothesis that the kinin B2 receptor could play a role during acute phase and the kinin B1 receptor, in chronic phase of inflammation.

Received May 15, 2000; revised August 8, 2000; accepted August 9, 2000.


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