TY - JOUR
AU - DSc, Antoni Stadnicki, MD,
AB - Abstract Tissue kallikrein cleaves kininogens to release kinins. Kinins mediate inflammation by activating constitutive bradykinin receptor-2 (BR2), which are rapidly desensitized, and induced by inflammatory cytokines bradykinin receptor-1 (BR1), resistant to desensitization. Intestinal tissue kallikrein (ITK) may hydrolyze growth factors and peptides, whereas kinins are responsible for capillary permeability, pain, synthesis of cytokines, and adhesion molecule-neutrophil cascade. Our and others results have demonstrated ITK in intestinal goblet cells and its release into interstitial space during inflammation. Kallistatin, an inhibitor of ITK, has been shown in epithelial and goblet cells, and was decreased in inflamed intestine as well as in plasma compared with noninflammatory controls. BR1 was upregulated in patients with inflammatory bowel disease (IBD), and it has expressed in an apical part of enterocytes in inflamed intestine, but in the basal part in normal intestine. ITK and BR1 were visualized in macrophages forming granuloma in Crohn's disease. In animal studies BR2 blockade decreased intestinal contraction, but had limited effect on inflammatory lesions. BR1 was found to be upregulated in animal inflamed intestine, in part dependent on tumor necrosis factor alpha (TNF-α). A selective BR1 receptor antagonist decreased morphological and biochemical features of experimental intestinal inflammation. Both BR1 and BR2 mediate epithelial ion transport that leads to secretory diarrhea. The upregulation of BR1 in inflamed intestine provides a structural basis for the kinins function, suggesting that a selective BR1 antagonist may have potential in therapeutic trial of IBD patients. (Inflamm Bowel Dis 2011) bradykinin, intestinal tissue kallikrein, kallistatin, kinin receptors, inflammatory bowel disease The kallikrein-kinin system is a part of the humoral defense system that participate in the inflammatory response. In mild, acute insults, kallikreins and kinins play a salutary role recruiting to the extravascular milieu proteases, acute phase proteins, and neutrophils. In severe inflammation, however, the same system amplifies the inflammatory cascade, and contributes to tissue destruction and chronic inflammation. There are two types of kallikreins, plasma and tissue; both serine protease enzymes may cleave kininogens to release kinins.1,2 A single gene codes for plasma kallikrein, which is synthesized in the liver, whereas tissue kallikrein is a member of a multigene family that shows different patterns of tissue specific gene expression.3,4 Plasma kallikrein exists as a zymogen, prekalliktein (PK), 75% of which circulates in the blood in a noncovalent complex with high molecular weight kininogen (HK). Under physiological conditions, tissue kallikrein is present in the highest concentration in exocrine glands, mostly in salivary glands and pancreas.5 In salivary glands tissue kallikrein occurs in active form, while in pancreas it is present as proenzyme.1 Both active and precursor forms are present in excretory product such as urine and sweat. Kallikrein purified from both rat and human colon was found to be biochemically similar, if not identical, to tissue kallikrein for salivary gland and pancreas.6 Plasma and tissue kallikreins differ in their molecular weight, isoelectric point, immunological properties, and substrate preference. Although HK is a better substrate for plasma kallikrein to release bradykinin, and low molecular weight kininogen (LK) is a better substrate for tissue kallikrein liberates kallidyn (Lys-bradykin), both are substrates for both plasma and tissue kallikreins.1 The major inhibitor of plasma kallikrein is C1-inhibitor, whereas kallistatin present in tissues and plasma is the main inhibitor of tissue kallikrein.7 HK is a multifunctional protein, β-globulin, with a plasma concentration about 80 μg/mL. HK consists of six domains divided into heavy chain (HK domains 1-3), and light chain (HK domains 5-6), linked by domain 4, which contains the sequence of bradykinin. LK is present in plasma and various tissues. LK is a β-globulin with a plasma concentration of 220 μg/mL; it has identical domain 1 through domain 4 of HK. However, LK domain 5 is completely different from HK and domain 6 is lacking.8 Plasma kallikrein releases nonapeptide, bradykinin from HK, while tissue and glandular kallikreins liberates decapeptide, kallidyn (Lys-bradykinin) from LK. Kallidyn is rapidly converted to bradykinin by aminopeptidase. Bradykinin has a short half-life, 30 seconds in circulation. Kinins are rapidly destroyed by kininases, which are present in blood and in tissues. Removal of its C-terminal arginine by kininase I (carboxypeptidase N) forms an active metabolite, des-Arg9 bradykinin, which has a half-life of ≈2 hours. Kininase II, known also as angiotensin-converting enzyme (ACE) to remove the COOH-terminal peptides, metabolizes kinins to their inactive forms.1,8 The final metabolite of bradyninin and des-Arg9-bradykinin is bradykinin.1,–5 T-kinins forming by cleavage T-kininogen were exclusively identified in rats.9 Bradykinin and kallidin and their active metabolites, des-Arg9-bradykinin and Lys-des-Arg9-bradykinin, respectively, bind to two transmembrane G-protein-coupled receptors designated bradykinin receptor-2 (BR2) and bradykinin receptor-1 (BR1).10 BR2 is constitutive mainly expressed in endothelial cells, stimulated by bradykinin to release nitric oxide and other negative regulators of smooth muscle tone and platelet function. However, BR2 might also be upregulated in the acute phase of inflammation.11 BR1 is inducible following tissue injury or after treatment with bacterial endotoxins or inflammatory cytokines such as interleukin-1 β (IL1-β) or tumor necrosis factor-alpha (TNF-α).12 Cytokine-induced BR1 expression is mediated by nuclear factor-κ β (NF-κ β) and specific MAP-kinase pathways (mainly p38 and JNK).13,14 The plasma kallikrein-kinin system is comprised of factor XII (Hageman factor) factor XI (initiator of intrinsic coagulation pathway), plasma PK and HK. Activation of the plasma kallikrein-kinin system produces plasma kallikrein by conversion of PK. Cleavage of HK by plasma kallikrein generates proinflammatory and proangiogenic bradykinin, and form biologically active kininogen fragment HKa.8 Products of this pathway induce a variety of inflammatory events. Plasma kallikrein in the presence of HK stimulates neutrophil aggregation15 and induces those cells to release elastase,16 and stimulates the cell-bound fibrinolytic system by converting prourokinase to urokinase.17 Recent studies show that HKa may stimulate in vitro secretion of cytokines; IL-1 β, IL-6, and TNF and chemokines from monocytes through signaling pathways by urokinase-type plasminogen receptor, integrin α-1 β2 (MAC-1) receptor, and complement protein C1q receptor.18 IL1-β release is localized to domain-3 and domain-5 of HK. In addition, HK and HKa have an-adhesive properties and HKa and domain 5 of HK inhibit angiogenesis.19 In the past two decades the role of the plasma kallikrein-kinin system in experimental and human sepsis20,21 and other acute inflammatory states including Rocky Mountain spotted fever,22 human experimental endotoxemia,23 and acute pancreatitis has been well delineated.8 In the 1990s we have developed an experimental model of enterocolitis induced by bacterial cell wall polymer peptidoglycan-polysaccharide from group A streptococci (PG-APS),24 originally created by Sartor et al.25 Female Lewis rats, the highest responders injected intramurally by PG-APS developed acute intestinal inflammation that peaks 1-2 days after PG-APS injection, gradually decreases over the next 10 days, and spontaneously reactivates beginning on day 14, accompanied by peripheral erosive arthritis, granulomatous hepatitis, normochromic anemia and leukocytosis, with histological findings of intestinal fibrosis and granulomas. Acute intestinal inflammation developed in all rat strains investigated, but chronic, transmural, granulomatous reactivation only in genetically susceptible Lewis rats, but not in Buffalo or Fisher rats. This model has unique features resembling Crohn's disease (CD). Inflammation is induced by an environmentally relevant antigen, is T-lymphocyte-dependent, has a spontaneous relapsing course, and has genetic background. Inflammation induced by APG-PS, similar to human inflammatory bowel disease (IBD), is mediated by a large number of inflammatory cascades and liberation of soluble mediators including cytokines, prostanoids, and activation of the kallikrein-kinin system. We have developed a specific plasma kallikrein inhibitor (P8720) to evaluate a direct relationship between the plasma kallikrein-kinin activation and inflammatory changes. We found that a specific kallikrein inhibitor decreased both acute and chronic granulomatous intestinal and extraintestinal inflammation, indicating that spontaneous reactivation of enterocolitis and extraintestinal inflammation is in part due to the plasma kallikrein-kinin activation in susceptible Lewis rats.26,27 This activation is not specific for PG-APS since we demonstrated that it can also be induced in a Lewis rat chronic enrerocolitis model induced by indomethacin.28 Looking for a functional mechanism involved in selective activation of the kallikrein-kinin system in genetically susceptible Lewis rats, we found that HK cleavage and yielding bradykinin by plasma kallikrein was faster in Lewis rat plasma than in Buffalo rat plasma and Fisher rat plasma.24 Because the rate of kallikrein formation and inhibition were similar in all rats investigated, we considered that the resistance of Buffalo and Fisher HK to cleavage may be caused by an intrinsic defect of HK. In the next study29 we found that a single point mutation at nucleotide 1586 translating from Ser511 (Buffalo and Fisher) to Asn511 (Lewis) is associated with N-glycolization, indicating that this molecular alteration may be one contributing factor resulting in chronic reactive colitis in Lewis rats. Later it was shown that HK-deficient rats injected with PG-APS develop only a minimal inflammatory response.30 Administration of PG-APS causes marked changes in host metabolism and activates many inflammatory cascades. A similar biological response is triggered by endotoxins (lipopolysaccharide [LPS]), which is detectable in plasma in most IBD patients during relapse,31 indicating that both bacterial products act through similar innate immunity activation, cytokines, and mediators.32,33 The results from experimental models prompted us to investigate whether the plasma kallikrein-kinin system is activated in human IBD. We demonstrated that in patients with ulcerative colitis (UC) in active disease phase (but not in inactive UC) there was moderate activation of this system as a significant decrease of plasma PK, HK, and functional levels of C1-inhibitor, and in some patients formation of kallikrein-inhibitor complexes on Western blot.34 However, Devani et al35 did not find this in plasma of patients with CD, probably due to the high plasma levels of C1-inhibitor. Nevertheless, this event may occur in plasma and, while reflecting the systemic inflammatory response, does not portray the actual events within the inflamed intestine. To evaluate the importance of the kallikrein-kinin system in the intestine it is important to consider the localization and function of ITK and other components of this system. The presence of kallikrein in the gastrointestinal tract has been observed since the 1960s,36,37 but little has been done to evaluate its role in IBD. Long ago only Zeitlin and Smith38 reported the presence of tissue kallikrein in normal human colon and a higher concentration in the inflamed colon of patients with UC. However, surprisingly, they located the enzyme mainly in colonic muscle, using a bioassay method based on kinin-forming activity in colonic tissue. To establish whether ITK plays a role in intestinal inflammation, we first turned to a rat model of PG-APS stimulated chronic inflammation resembling CD.39 We showed that the normal location of ITK was the goblet cells and substantial amounts of ITK were present in the macrophages of the granulomas found in the submucosa, indicating that ITK is present at the site of inflammation. Despite an additional source for tissue kallikrein from macrophages, which could contribute to the total antigenic tissue kallikrein level of the affected gastrointestinal tract, we found that ITK concentrations were markedly reduced in the inflamed cecum as compared with the normal cecum. Thus, we measured ITK mRNA in normal and inflamed colon to investigate whether the decrease in ITK level in inflamed colon is related to its lower synthesis or reflect its release during PG-APS-induced inflammation. Since the decrease of ITK protein concentration was associated with unchanged ITK mRNA levels, its reduction was not due to suppression of its gene expression. Further evidence that inflamed intestinal tissue cells had secreted ITK to a greater extent than normal, we obtained from an in vitro culture study evidence of a marked ITK decrease in supernatant of inflamed intestine (Table 1). In addition, we found that a potent tissue kallikrein inhibitor, kallikrein-binding protein in the rat (whose human homolog is kallistatin) was decreased in rat plasma during inflammation (Fig. 1), suggesting release ITK into plasma. Thus, our results imply increased in vivo release of ITK in the course of inflammation induced by PG-APS. We postulated that if the rat model resembled human IBD, many of the same things would occur in human IBD as in experimental rat enterocolitis. In human studies40,41 we demonstrated that ITK was in goblet cells in normal and inflamed human colon, which was in agreement in our previous findings in rats (Fig. 2). We again found that ITK levels were significantly decreased in inflamed intestinal tissue from patients with IBD compared to normal controls, consistent with its secretion in vivo. The immunostaining of the crypt luminal contents in normal physiological conditions suggested that ITK is in part released into the lumen. In human IBD studies we were able to more closely examine the kallistatin, a specific inhibitor, naturally occurring serine protein inhibitor (serpin) of human tissue kallikrein. We were able for the first time to localize kallistatin to epithelial cells (Fig. 2). Kallistatin apparently colocalizes within ITK in the macrophages within the granulomas. Finally, we observed the decrease of kallistatin in inflamed intestinal tissue using two different methods. We showed decreased plasma levels of kallistatin also in IBD patients, similar to kallikrein-binding protein in rat enterocolitis, which indicated that the secretion of ITK results in an active form since kallistatin only stochiometrically combines with the enzymatically active tissue kallikrein. The resulting complex resulted in a decrease of the inhibitor. In fact, Xiong et al42 demonstrated that the half-life of kallikrein-binding protein-tissue kallikrein complexes in the inflamed rat plasma is ≈4-fold higher than the half-life of inhibitor alone. We also observed a colocalization of TK and kallistatin in endothelium of intestinal vessels, similar to the observation of Wolf et al.43 The cellular colocalization of kallistatin and tissue kallikrein have been observed in human pancreas, kidney, and salivary glands, which indicate that kallistatin controls tissue kallikrein activity.5,44 Localization of epithelial ITK to goblet cells was similar to intestinal trefoil factor, which is also decreased during intestinal inflammation,45 presumably due to goblet cell expulsion of mucus and associated proteins. It has been indicated that the goblet cells may have a more active role in the regulation of intestinal homeostasis and immunologic processes by interaction with other cells such as macrophages and lymphocytes.46 Table 1 Tissue Kallikrein Level in Cultured Intestinal Samples In Vitro     View Large Table 1 Tissue Kallikrein Level in Cultured Intestinal Samples In Vitro     View Large Figure 1 View largeDownload slide Plasma level of kallikrein-binding protein (KBP, analog of human kallistatin). Levels of KBP in rat plasma are expressed in micrograms per milliliter (means ± SD). *P < 0.01, **P < 0.001). Solid bars, control groups; hatched bars, PG-APS-injected groups (used with permission from Ref. 39). Figure 1 View largeDownload slide Plasma level of kallikrein-binding protein (KBP, analog of human kallistatin). Levels of KBP in rat plasma are expressed in micrograms per milliliter (means ± SD). *P < 0.01, **P < 0.001). Solid bars, control groups; hatched bars, PG-APS-injected groups (used with permission from Ref. 39). Figure 2 View largeDownload slide Immunolocalization of ITK and kallistatin in normal colon and colonic tissue of human IBD. (A) ITK in goblet cells of normal colon (×312). (B) ITK in goblet cells of CD colon (×312). (C) ITK in goblet cells of CD colon (×780). (D) Kallistatin in epithelial cells of normal ileum. (×312). (E) Kallistatin in epithelial cells as well as in plasmocytes of CD ileum (×312). (F) ITK in macrophages within granuloma (×780) (used with permission from Ref. 40). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Figure 2 View largeDownload slide Immunolocalization of ITK and kallistatin in normal colon and colonic tissue of human IBD. (A) ITK in goblet cells of normal colon (×312). (B) ITK in goblet cells of CD colon (×312). (C) ITK in goblet cells of CD colon (×780). (D) Kallistatin in epithelial cells of normal ileum. (×312). (E) Kallistatin in epithelial cells as well as in plasmocytes of CD ileum (×312). (F) ITK in macrophages within granuloma (×780) (used with permission from Ref. 40). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] The factors that determine ITK secretion and activation are still not defined. Fasth and Hulten47 indicated that ITK secretion is largely under cholinergic control; however, during inflammation this process may be far more complex. It is known that inactive tissue prokallikrein can be activated by trypsin, plasmin, or even plasma kallikrein.1 Such enzymes could enter the intestinal space through several routes: by transudation of plasma or release from inflammatory cells. Interestingly, our data indicated that secreting macrophages could contribute significantly to levels of ITK. In all probability a proinflammatory effect of ITK in the intestine is due to macrophage production and secretion. Figueroa et al48 demonstrated tissue kallikrein on human blood neutrophils, but did not detect the enzyme in monocytes. It is possible that tissue kallikrein is only expressed in stimulated monocytes or macrophages, as is the case for tissue factor.49 However, luminal ITK may enter the inflamed mucosa due to enhanced permeability, where it could hydrolyze growth factors and peptides which could act on the epithelial mucosa cells. In fact, recently Devani et al50 demonstrated that ITK immunoreactivity was significantly weaker in goblet cells in both CD and UC patients, but with strong reactivity in intestinal interstitium of IBD patients. In addition, they showed ITK and kallistatin depletion in goblet cells and that increased interstitial reactivity correlated with the degree of intestinal inflammation. Once activated, ITK can cleave LK, which is present in intestine as well as both LK and HK, which are present in plasma and likely present in the protein-rich exudates of the inflamed intestine. Interestingly, cleavage of LK by neutrophil elastase renders the protein a better substrate of plasma kallikrein to liberate bradykinin and Lys-bradykinin.51 Apart from its kininogenase activity, tissue kallikrein has been implicated in the processing of growth factors and peptide hormones. Tissue kallikrein hydrolyzes vasoactive intestinal peptide and procollagenase in vitro.52 If these reactions occur in vivo, ITK itself, independently of kinins action, may influence intestinal motility, secretion, and connective tissue metabolism. In addition, tissue kallikrein may directly activate BR2, independent of bradykinin release.53 Thus, in addition to thrombin and trypsin, which can affect tissues by activating a novel family of protease activated receptors (PARs 1-4), tissue kallikreins represent a PAR regulator, and consequently BR2 may belong to a new group of PARs. Recent investigation revealed that PAR1 and PAR2 are present on intestinal epithelium and PAR1 has been shown to mediate intestinal secretion.54 Despite these results there are many questions to be answered. What is the mechanism of ITK activation? Does ITK mediate intestinal inflammation mainly by LK cleavage to release kinins or are other ITK-related pathways significantly involved? Is the plasma kallikrein-kinin system activated in intestinal circulation during IBD; and if so, what is the role of HKa to maintain inflammation? At the onset of inflammatory insult tissue kallikreins cleave kininogens, releasing kinins. Almost 50 years ago Lewis demonstrated for the first time that bradykinin was able to evoke cardinal signs of inflammation.55 Bradykinin administration mediates two of the cardinal signs of inflammation (rubor, color) through the activation of BR2 that causes vasodilatation due to nitric oxide and prostanoids production by endothelial cells. Increased vascular permeability leads to ensuing exudation of protein-rich fluid, causing a third sign, swelling (tumor). In addition, in chronic inflammation BR1 seems to be important in neutrophil accumulation in inflamed tissue.56 Both BR1 and BR2 are involved in the onset and maintenance of nociceptive alterations and inflammatory pain perceptions (dolor) as the fourth cardinal sign of inflammation.57,58 It should be noted that research on involvement of BR2s in inflammatory states has progressed more quickly than that on BR1s. Thus, the role of BR2s, but not BR1s, in inflammatory processes was widely explored during the 1990s.12,59 This was favored by the systematic development of selective peptidic BR2 antagonists by the pharmaceutical companies; at that time the industry believed that by BR2s were more attractive as pharmacological targets for the possible treatment of pathological states. Thus, in order to visualize the BR2s that mediate the proinflammatory effect of kinins, we first employed immunohistochemistry with antibodies to specific amino acid (peptides) sequences in the receptor. Unfortunately, antibodies against the inducible BR1 were not available at that time. We described for the first time BR2 distribution in the intestinal layer. BR2 was shown in epithelial cells, smooth muscle cells, and in serosa.28 We have shown that expression of BR2 was enhanced in the intestinal tract during the indomethacin-induced intestinal inflammation in Lewis rats. Because kallikrein blockade also inhibits kininogen activation and the release of bradykinin, it was important to determine the precise pathophysiological mechanisms of these in vivo observations. As noted earlier, both kallikrein and bradykinin have well-documented proinflammatory activities. The availability of a selective BR2 antagonist offered a means to address the relative roles of these two mediators. Thus, we used a specific bradykinin BR2 antagonist (HOE-140) in a PG-APS-induced model of granulomatous enterocolitis and associated arthritis.60 However, we found that BR2 blockade attenuated arthritis but exhibited only a minimal preventive effect on enterocolitis, suggesting that kinin stimulation via BR2 was more important in arthritis than enterocolitis in this model. Later, Arai et al61 used a dextran sulfate-induced colitis model in mice to show that a selective BR2 antagonist suppressed shortening of the large intestine, which was in agreement with later results indicating that intestinal contraction was regulated by BR2.62 However, other findings from the Arai et al study demonstrated only a limited effect in intestinal inflammatory lesions by BR2 blockade. To establish whether kinins play a role in IBD we carried out human studies. Our results63 demonstrated the alterations in both the distribution and levels of BR1 and BR2 in both protein and mRNA in patients with IBD compared to controls. We demonstrated the increase in the ratio of BR1 to BR2 gene expression in relation to the degree of intestinal inflammation (Table 2). We visualized both BR1 and BR2 in normal as well as inflamed human colon and ileum (Fig. 3). BR2 was observed in the epithelial cells, mostly in the apices of enterocytes of the normal human colon. However, BR2 was present mainly intracellularly and in the basal part of enterocytes in inflammatory UC tissue. In addition, BR2 was shown in the endothelial cells of blood vessel walls in the colonic submucosa. In striking contrast, BR1 was localized in the epithelial cells of normal colon, mainly immunostained in the basal part of enterocytes. BR1 was shown in the gladularis mucosa of UC-inflamed colon as well as in enterocytes in CD inflammatory tissue as positive staining in the apical part of enterocytes as well as intracellularly. In addition, BR1 was observed in the nerve of the colonic submucosa. Importantly, BR1 but not B2 was present in macrophages inside granulomas of CD intestine. The image analysis revealed that the total level of BR1 was significantly higher in enterocytes of patients with active phase UC as well as in CD as compared with controls. BR1 was also constitutively expressed in normal colonic epithelium, possibly because the normal bacterial flora activated the innate immune system, but was remarkably upregulated by inflammation. Recent studies have demonstrated that the BR2 receptor may be recycled several times in the same enterocytes after internalization.64,65 This process was supported by the appearance of BR2 intracellularly in some enterocytes in UC intestine. In contrast, BR1 normally do not internalize following agonist stimulation, but they seem to translocate and aggregate after agonist binding, probably to facilitate the amplification of B1 receptor-mediated responses.66 Taken together, our results strongly indicated that the BR1 receptor is a major structural background for kinins function in IBD. Kinins are involved in intestinal glucose and electrolyte transport and local blood flow under normal conditions. However, in intestine kinins may be more important as pathophysiological mediators.67 Zipser et al68 showed that bradykinin produces 2-4-fold greater concentration of prostanoids in animals with experimental colitis than in normal controls, which may contribute to the increased intestinal secretion of chloride. However, kinins may also act through a direct effect on secretion by epithelial cells. Manning et al69 reported that bradykinin-induced chloride secretion by the guinea pig ileum occurs by direct binding of the ligand to its receptor. It has been shown that both inducible BR1 and constitutive BR2 mediate the ion transport in intestinal epithelium. Cuthbert et al70,71 demonstrated that the secretion of chloride into the lumen is accompanied by natrium secretion and in turn water, thus leading to secretory diarrhea. It should be noted that this effect of kinins is very prostaglandin-independent. Kinin BR1 is more resistant to desensitization than BR2; thus, in all probability BR1 participate mainly to induce clinically significant diarrhea. In relation to IBD, kinins may act on endothelial cells, smooth muscle cells, epithelial cells, and fibroblasts, which stimulate cell response through G-protein-coupled kinin receptors. It is known that activation of transcriptional factor NF-κ β stimulates expression of numerous molecules relevant to the pathogenesis of IBD, including IL1-β, TNF-α, IL-6, IL-8, ICAM-1, and other adhesion molecules.32 Recently it has been shown that upregulation of BR1 in the trinitrobenzene sulphonic acid (TNBS)-induced colitis model is in part dependent on NF-κ β activation.72 In addition, Ni et al13 have demonstrated that an NF-κ β-like binding site on the human BR1 seems to be essential for the control of receptor transcription following exposure to certain inflammatory agents such as IL-1 β, TNF-α, or LPS. Taken together, these data indicate the participation of NF-κ β in BR1 expression in IBD. By opening the tight junctions between endothelial cells, kinins can increase capillary permeability.67 Recent results indicate that kinins stimulate through BR2 inflammatory cell adhesion molecules, and white blood cells migration to extravascular space. Then BR1 is induced and its stimulation promotes more cell adhesion molecules, cells influx mainly neutrophils, and to a lesser extent mononuclear cells.10,56,73 Interestingly, BR1 has been immunolabeled in circulating neutrophils.74 Kinins may act as mitogens to increase DNA synthesis, thereby promoting cell proliferation.59 The ability of kinins to stimulate fibroblast proliferation may contribute to fibrosis in chronic intestinal inflammation.75 Of particular importance is the ability of kinins to stimulate macrophage release of IL-1 and TNF-α.76 This effect is probably mediated by stimulation of BR1, since a specific BR1 antagonist blocks kinin-induced cytokine release. In our human study we demonstrated a positive staining for TK, kallistatin, and BR1 (but not BR2) in macrophages forming granuloma and for BR1 in plasmocytes in the border of granuloma. This observation emphasizes the close relationship between the immune responses important in IBD and the inflammatory mediators including the ITK-kinins. Kinins may also evoke pain by stimulating sensory nerves to mechanical stimuli and other chemical mediators, such as histamine and serotonin, and, in turn, causes hyperalgesia.57 The role of BR1 and its agonists in inflammatory pain has been shown in animals.58 Interestingly, across the intestinal layer we observed expression of BR1 not only in mucosa and muscle cells but also in enteric nerves. A report by Stanley and Philips77 indicated that bradykinin accelerates mucin discharge from goblet cells. Although it is not know if ITK is cosecreted with mucin after bradykinin action, it raises the possibility of a positive feedback loop between local ITK release and bradykinin generation. Independently, human UC is associated with depletion of colonic intracellular mucin stores.78 Local formation of kinins would contribute to this effect. In some cases BR1 upregulation appears to be secondary to the downregulation of BR2.79 It is possible that such a kinin receptor profile may be related to colorectal polyps, since we found in another study high BR1 mRNA and BR1 protein (but not BR2) in adenomas, but in contrast the increase expression of BR2 mRNA, and protein only in hyperplastic polyps.80 It has been established that BR1 and BR2 genes are both located at the same chromosome of human chromosome 14, mice chromosome 12, and in rat chromosome 6, which may also contribute to balanced regulation of both receptors.81 Bachvarov et al82 demonstrated a BR1 polymorphism in human IBD, but its clinical significance remains unknown. The influence of kallikrein-kinin on angiogenesis has recently been appreciated. Kinins promote angiogenesis by upregulation of basic fibroblast growth factor through BR1 or by stimulation of vascular endothelial growth factor (VEGF) formation by BR2.19 Kinins act synergistically with transforming growth factor β-1, which is known to be involved in inflammatory and repair processes in IBD.83 Monoclonal antibody C11C1, which prevents binding HK to endothelial cells, also limits its conversion to bradykinin, thus downregulating angiogenesis.84 In addition, local tissue delivery of human TK gene accelerates angiogenesis needed for wound healing in a mouse model of ischemia.85 A recent study by Danese et al86 in patients with IBD demonstrated direct evidence that angiogenesis has a role in the pathogenesis of both UC and CD, showing a higher density of microvessels within intestinal mucosa and submucosa and increased expression of αvβ3-integrin in endothelium with a simultaneous increase of VEGF expression within intestinal mucosa in the active IBD phase. Our most recent data87 also demonstrated the increase of gene expression as well as protein levels for VEGF and its receptors in active inflammatory colonic tissue and increased VEGF levels in serum and plasma in active UC patients. It is possible that kinins and ITK as proangiogenics may in part promote angiogenesis in IBD, although the interaction between the kallikrein-kinin systems and growth factors is highly complex and requires further investigation. In contrast, HKa or its domain 5 inhibit the endothelial cells migration and proliferation needed for angiogenesis.88 However, LK does not display any antiangiogenic activities exhibited by HKa, supporting the hypothesis that domain 5 is the effective region for the antiangiogenic activity of HKa. Table 2 Expression of Gene Encoding B1R and B2R     View Large Table 2 Expression of Gene Encoding B1R and B2R     View Large Figure 3 View largeDownload slide Immunolocalization of kinin B1 and B2 receptors in human normal and IBD colonic tissue. (A) B2 receptor in enterocytes of UC colon. Specific staining mainly in basal part of enterocytes; ×360. (B) B1 receptor in epithelial cells of normal colon; ×280. (C) B1 in enterocytes of CD colon. Positive reaction mainly in apical part of the cells; ×560. (D) Specific staining for B1 in nerves localized in UC colon; ×280 (used with permission from Ref. 63). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Figure 3 View largeDownload slide Immunolocalization of kinin B1 and B2 receptors in human normal and IBD colonic tissue. (A) B2 receptor in enterocytes of UC colon. Specific staining mainly in basal part of enterocytes; ×360. (B) B1 receptor in epithelial cells of normal colon; ×280. (C) B1 in enterocytes of CD colon. Positive reaction mainly in apical part of the cells; ×560. (D) Specific staining for B1 in nerves localized in UC colon; ×280 (used with permission from Ref. 63). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] In recent years the role of BR1s in inflammatory processes was explored by development of nonpeptidic, highly selective BR1 receptor antagonists.10,12 In addition, the generation of BR1 knockout mice achieved in the 2000s gave more molecular approaches to look into receptor-ligand interaction and cellular molecular signaling.89 The recent study of Hara et al72 investigated the role of BR1s in a TNBS-induced mouse model of colitis. They demonstrated for the first time that selective, orally active, nonpeptide BR1 antagonist SSR240612 markedly reduced TNBS-induced colitis, e.g., intestinal tissue damage and neutrophil influx. The beneficial effects of treatment have been shown in both preventing colitis and decreased inflammation in established colitis. The functional upregulation of BR1 was dependent on de novo protein synthesis. Importantly, Hara et al clarified evidence that TNF-α may upregulate BR1 expression in the TNBS colitis model. It is possible that anti-TNF-α monoclonal antibodies may in part modulate IBD by regulation of BR1 expression. Our data from a human study showing alteration in the distribution of BR1 and significantly increased levels in patients with IBD tend to corroborate the Hara et al results, suggesting that selective BR1 receptor antagonist may have potential in therapeutic trial. It should be noted that kinins are implicated in the regulation of blood pressure, sodium homeostasis, and the cardioprotective effect of preconditioning.90 Angiotensin-converting enzyme (kininase II) inhibition increases blood levels of bradykinin and kallidin peptides.8 Thus, the potentially salutary role of kinins in the circulation does not encourage systemic administration of BR1 antagonist. In fact, the commonly used ACE inhibitors are cardioprotective in part by elevating bradykinin, and thus increasing nitric oxide as well as decreasing angiotensin II formation.8 Most recently, Marceau and Regoli91 suggested that topical drug delivery to the intestine such as for 5-ASA compounds to avoid side effects may be appropriate for the management of IBD. The importance of ITK in the intestine mainly depends on the secretion of active enzyme in the presence of kininogens, especially LK, with subsequent kinins generation. Kininogen has been demonstrated in both normal and inflamed human colon38; thus, ITK can generate kinins. In addition, kallistatin, a major tissue kallikrein inhibitor, and kininase II, a kinin inactivator, have been demonstrated in intestinal tissue.1,92 Thus, all components necessary for kinin action are present in the intestine. In fact, the levels of kinin peptides in tissue were higher than in blood, suggesting the primary tissue localization of the kallikrein-kinin system.2 Kinins have been demonstrated to stimulate synthesis of eicosanoids, nitric oxide, and cytokines by white blood cells, endothelial cells, and epithelial cells, and promote the adhesion molecule-neutrophil cascade known to be important in IBD. The receptors for these reactions are present in the human intestinal layers and thus kinins can initiate these inflammatory reactions in the inflamed ileum and colon. Acknowledgements I thank Professor Dr. R.W. 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TI - Intestinal tissue kallikrein-kinin system in inflammatory bowel disease
JO - Inflammatory Bowel Diseases
DO - 10.1002/ibd.21337
DA - 2011-02-01
UR - https://www.deepdyve.com/lp/oxford-university-press/intestinal-tissue-kallikrein-kinin-system-in-inflammatory-bowel-mMyl55RrbM
SP - 645
EP - 654
VL - 17
IS - 2
DP - DeepDyve
ER -