Study of the expression of cd68+ macrophages and cd8+ t cells in human granulomas and periapical cysts



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Study of the expression of CD68+ macrophages and CD8+ T cells in human granulomas and periapical cysts.
Rodini CO, Lara VS.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001 Aug;92(2):221-7

Commentary
Evolution from granuloma to cyst: possible mechanisms involved in epithelial proliferation of Malassez rests.
Antonio Schütz, Ph.D.
Dentist, Pharmacist, Master in Oral Pathology at the Federal University of Rio de Janeiro (UFRJ), Doctor in Oral Pathology for the Bauru School of Dentistry, University of Sao Paulo (FOB/USP), Brazil.  Address reprint request to Dr. Antonio Beltrao Schütz, José Bonifácio 2598/103, telephone: (5555) 3221-6763, CEP: 97015-450, Santa Maria, RS, Brazil. Email: vapschutz@hotmail.com

Last revision: Mai 21, 2007.


With relation to Professor Lara, we first meeting was in the memorable reunion of the Brazilian Society of Stomatology, in Curitiba, 1988. In that time, was student of the first year of post-graduation in Oral Pathology at the Federal University of Rio de Janeiro (FOUFRJ), at the staff of the professor José Carlos Borges Teles, ex-student at the Indiana University, and Professor Lara, student of the last year of graduation at FOB/USP, presented a clinic case organized by Professor Consolaro. As disagree of an aspect of the presentation, asked her; responding me, “I do not know”. Moment in that thought, “She will certainly be a Brazilian professor”. My prevision confirmed itself. After some years, again, meet us at the Department of Pathology at Bauru School of Dentistry at Sao Paulo University (FOB/USP). Coursed the first year of my doctoral study (Ph.D.) in Oral Pathology, and Professor Lara finished her mastered study.

As in our first meet, disagree of the conclusion of Rodini; Lara (2001),1 affirming that in the advanced stage of periapical granulomatous lesions, among the population of leukocytes, would predominate OKT8+ cells with suppressor phenotype, implicating in a state of immune suppression associated with the formation of periapical cyst (p. 226). Contrarily, this state of immune suppression would explicate the concept of “dormancy”, where the differential expression of key cell surface antigens on oral epithelial cells may keep to recruit immune effectors cells in a state of unresponsiveness; thus, contributing to the long quiescent period observed in many periodontal and endodontic lesions (Han; Huang; Lin ; Warner et al., 2003).2 Other data contrasting with the CD8+ suppressor phenotype was the identification of periapical lesions of chemokines RANTES, IP-10, and MCP-1 (Silva; Garlet; Lara; Martins et al., 2005),3 since IP-10, preferentially, attracts activated CD4+ Th1 cells; activated Th1 cells stimulate natural killer cells or macrophages to kill tumor cells or to stimulate dendritic cells to prime cytotoxic T cells. Thus IP-10 contributes to killing tumor cells via activated Th1 cells (Kanda; Watanabe, 2002),4 as well as, in periapical lesions, presents anti-proliferative effect to epithelial cells, explicating also, at least in part, the long period of “dormancy” of Malassez epithelial rest, which is possivebly, partially, disturbed for the increase of the local concentration of nitirc oxide causing dowregulation of the production of IP-10.

In development and progression from granuloma to cyst were detected high levels of IFN-gamma in all samples, after cell stimulation with phorbol myristate acetate and Ca(2+) ionophore, which were not statistically different from the levels of IFN-gamma in PB-MNC cultures. IL-4 was detected in 76% samples, but its concentrations were much lower than in PB-MNC samples. The levels of IFN-gamma were higher in cultures of PL-MNC isolated from periapical lesions with predominance of T cells (T-type lesions) and correlated positively with the proportion of antigen-presenting cells (macrophages and dendritic cells), CD4(+) T cells and IgG2(+) B cells/plasma cells. The levels of IL-4 correlated negatively with the proportion of macrophages, but positively with the number of mast cells and IgG4(+) cells. IL-18Ralpha, a stable marker of Th1 cells, was detected on a relatively small proportion of CD3(+) T cells and its expression correlated with the levels of IFN-gamma. However, the expression of ST2L, a stable Th2 cell marker, was not detected. The levels of Th1 and Th2 cytokines did not correlate with clinical characteristics of the lesions, defined for the presence of symptoms, concluding that the results suggested the predominance of Th1 immune response in periapical lesions (Colic; Lukic; Vucevic; Milosavljevic et al., 2006)5.

Similar results there was been yet verified by Liapatas; Nakou; Rontogianni, 2003.6 No statistically significant differences were detected in the inflammatory infiltrate between periradicular granulomas and cysts. The T4/T8 ratio ranged approximately from 1 to 3 and greater, being consistent with inflammation of periradicular tissues. The final differentiation of B lymphocytes to plasma cells was also detected, whilst natural killer (NK) cells were found in only 10 cases (22%). Moreover, antigen presenting cells and T suppressor/cytotoxic cells were found to be associated with both pre-existing and newly formed epithelium. These results suggested that periradicular granulomas and cysts represent two different stages in the development of chronic periradicular pathosis as a normal result of the process of immune reactions in which B-lymphocyte and T-lymphocyte-mediated immunologic reactions have been implicated and that can not be inhibited;4 in spite of the endodontic treatment not only to stop the invasion of injurious factors but also proliferation of epithelium (Yanagisawa, 1980).7

In a study about the identification of the various subpopulations of T-lymphocytes identified in periapical lesions was verified the presence of T-cells, indicating the participation of cell-mediated reactions in their pathogenesis, considering that 14 of 15 periapical lesions stained themselves positively for pan T-lymphocytes (T11), T helper cells (T4), and T cytotoxic cells (T8) (Barkhordar; Desouza, 1988)8.

Other data that support the activation of the immune response in the final stage of the evolution from granuloma to cyst, and not its suppression, is the accentuated presence of Langerhans Cells in subepithelial localization of epithelial granulomas suggesting that LCs appeared to be associated with T lymphocyte infiltration (relation CD4/CD8 positive) and with the proliferative potential of the epithelial tissue in periapical lesions (Suzuki; Kumamoto; Ooya; Motegi, 2001)9.

In addition, monocytes/macrophages were associated with the majority of periapical granulomata, dental developmental cysts being present in all periapical cysts. Langerhans cells, intraepithelial lymphocytes, and monocytes/macrophages were found in some epithelia within periapical granulomata and in the majority of the epithelial linings of odontogenic cysts. Increased numbers of immune cells were seen around proliferative epithelia and adjacent to the epithelial linings of cysts suggesting that cell-mediated and humoral immunoreactions occur in these lesions and may be associated with the epithelial proliferation within the periapical lesions (Gao; Mackenzie; Rittman; Korszun et al., 1988).10

Of course, there are some articles publishing the greater presence of cells OKT8+ (CD8) than OKT4 (CD4)4,11 Similar conclusion to Rodini; Lara (2001)2 was made by Levine; Witherspoon; Gutmann; Nunn; et al., (2001),12 in a study about the effect of feline immunodeficiency virus (FIV) on CD4+ and CD8+ counts in periradicular lesions using immunohistochemical staining for CD4+ and CD8+ receptors, having been verified a significantly lower CD4+ counts and CD4+/ CD8+ ratios, observed at all time periods in the periradicular region of the FIV group (P = 0.0006).

In spite of the presence of IgE producing cells, the morphological picture of mast cells would not suggest the presence of anaphylactic reaction in periapical granulomatous lesions. Moreover, the diffuse distribution of T lymphocytes with the prevalence of T-suppressor/cytotoxic over T-helper lymphocytes, and not numerous macrophages in the inflammatory infiltrates would not also suggest the participation of a typical cell-mediated immunity reaction in the development of periapical granulomas. Numerous T-suppressor/cytotoxic lymphocytes and low numbers of macrophages could be important factors of chronicity of the periapical inflammatory diseases (Babal; Brozman; Jakubovsky; Basset et al. (1989).13 However, in this work, was studied a greater number of dental abscesses or granulomas secondary infected in evolution to abscesses; explicating, at least in part, the decreased number of macrophages, as well as the prevalence of T suppressor cells over T helper cells. Possibly, the same may have occurred in the study of Rodini; Lara (2001).2



In the big majority of the published articles, the cellular population predominant, in periapical granulomas, was monocytes/macrophages, particularly, in lesions that showed a positive reaction to percussion or were tender on palpation than in lesions without these symptoms. (Matsuo; Ebisu; Shimabukuro; Ohtake et al., 1992)

Macrophages, lymphocytes, and endothelial cells expressed RAGE; and these cellular types, in addition to plasma cells, also exhibited anti-iNOS immunoreactivity, suggesting that in periapical lesions there is an interaction between the presence of the receptor for advanced glycation end products (RAGE) and inducible nitric oxide synthase (iNOS), with relation to production of nitric oxide (NO) (Hama; Takeichi; Saito; Ito, 2007).14 This mediator influences the processes of proliferation and differentiation of epithelial cells; thus, resembling effects mediated by protein-type factors EGF and KGF (Krischel et al. 1998).15 In addition, was suggested that NO might promote the progression of periapical lesion by inducing apoptosis of macrophages and osteoblasts (Lin; Kok; Lin; Wang et al., 2007).16

Epithelial cell proliferation is often observed in periapical lesions of endodontic origin. However, the mechanisms that stimulate the epithelial cell rests of Malassez to proliferate are not understood fully. In periapical lesions without epithelial cell proliferation has been identified a weak immunoperoxidase staining or low specific binding of 125I-EGF, whereas in periapical lesions with epithelial cell proliferation and cyst formation has been identified a strong immunoperoxidase staining in the epithelial cells or high specific binding of 125I-EGF (Lin LM, Wang SL, Wu-Wang C, Chang KM, Leung C, 1996).17

Keratinocyte growth factor (KGF) was recently identified as a growth factor that is produced by stromal fibroblasts that acts specifically stimulating the epithelial growth and differentiation. KGF-expressing cells were found in the connective tissue stroma closed to dense foci of inflammatory cells, of proliferating epithelial elements and of cystic epithelial linings, suggesting that the induction of KGF expression in the stromal cells of periapical lesions might play an important role in the stimulation of the epithelial proliferation associated with cyst formation (Gao; Flaitz; Mackenzie, 1996)18.

Fibroblast growth factor is of a class of heparin-binding growth factors that has been implicated in the stimulation of the endothelial cell proliferation, migration in vitro and angiogenesis in vivo. An immunopositive, cytoplasmic, and nuclear reaction for basic fibroblast growth factor with varying degrees of upregulation has been identified in periapical lesions indicating that a local rise in the tissue level of basic fibroblast growth factor might play an important role in the pathogenesis of chronic apical periodontitis and periapical cysts (Moldauer; Velez; Kuttler, 2006),19 resultant of the link of FGF in receptors on ME (epithelial cells) dominantly bind to FGF-1 and FGF-7/KGF, which transduce their signals via FGFR2-IIIb (Yamanaka; Sakamoto; Tanaka; Zhanget al., 2000 ).20

Therefore, proliferation of the epithelial rests of Malassez to form the lining of inflammatory dental cysts induced by these growth factor appears to be associated with a change from an unusual epithelial phenotype to that of a stratified non-cornifying epithelium in which some epithelial keratins are coexpressed, considering that the immunocytochemistry and a panel of monoclonal antibodies directed against various keratin polypeptides indicated that (a) keratin 19 was expressed by all epithelia; (b) rests of Malassez also expressed keratin 5 but not large amounts of other keratins; and (c) epithelial proliferation in periapical lesions was associated with increased expression of keratin 14, a marker of stratifying epithelia, new expression of keratins 4 and 13, differentiation markers for non-cornifying epithelia and variable, low levels of keratins 8 and 18, markers of simple epithelia (Gao; Mackenzie; Williams; Cruchley et al., 1988).21

The epithelial rests of Malassez (ERM) verified inside granulomatous tissue are derived from the disintegrating epithelial root sheath of Hertwig that guides root formation during tooth development. Low concentrations of nitric oxide (NO) produced by NO-synthase I (NOS I) and NOS III activate intracellular soluble guanylate cyclase (sGC) to produce intracellular cyclic guanosine 3':5'-monophosphate (cGMP), which triggers rapid cellular responses such as cell proliferation, cell differentiation, and apoptosis under physiological conditions (Korkmaz; Bloch; Behrends; Schroder et al., 2004).22 The basal production of NO by eNOS, in Mallassez epithelial rests, is modulated by phosphorylation of eNOS at Ser1177 and Ser116 residues, while the basal activity of eNOS is not influenced by phosphorylation of eNOS at Thr495 residue, proving evidence that phosphorylation plays a key role for regulation of the catalytic activity of eNOS (Korkmaz; Bloch; Addicks; Schneider; Baumann et al., 2005).23

Samples of radicular cyst-lining epithelium, which is considered to be identical to the cell rests of Malassez, might play a role in the apical cyst formation for the interaction with surrounding connective tissue or hematopoietic cells through the expression of various cytokines, growth factors and epithelial cell growth-related receptors by RT-PCR. All samples studied expressed IL-1alpha, -1beta, IL-6, IL-8, IL-11, TGF-beta1, PDGF-A and aFGF, and receptors for EGF (c-erbB), KGF, HGF (c-met) and IL-6. Some of the specimens expressed MIP-1alpha, RANTES, GM-CSF, M-CSF, TNF-alpha, PDGF-B and bFGF, but no expression of IL-2, IL-4, IFN-gamma, IGF-I, EGF and KGF was detected (Ohshima; Nishiyama; Tokunaga; Sato et al., 2000).24

Heat shock protein (HSP) is a small HSP family that plays part in the regulation of epithelial cell growth and differentiation, wound healing, apoptosis and cell protection against inflammatory cytotoxicity mediators. The expression of HSP27 was investigated immunohistochemically in periapical granulomas with epithelial rests of Malassez and in radicular cysts. Anti-HSP27 mouse monoclonal antibody and peroxidase-labeled streptavidin-biotin standard technique were used to study the expression of HSP27. Proliferating epithelial cell rests, and islands of epithelium and epithelial lining of microcysts strongly reacted in all layers, whereas radicular cysts epithelial lining presented mainly a moderate suprabasal staining pattern. However both the proliferating epithelial cell rests and radicular cysts shared an over-expression of HSP27 immunostaining intensity in coincidence with the presence of local infiltration of immune cells (Leonardi; Villari; Caltabiano; Travali, 2001).25

HSP60 was detected in some lymphocytes of granulation tissue and in lining epithelium of periapical inflammatory lesions, whereas Malassez epithelial rests showed no staining for HSP60. Epithelial HSP60 reactivity was more intense in RCs than in RRCs. HSP70 was expressed in lymphocytes, endothelial cells and lining epithelium of periapical inflammatory lesions and in Malassez epithelial rests. The staining intensity of HSP70 in Malassez epithelial rests was slightly lower than that in lining epithelium of RCs and RRCs.7

Bacterial heat shock protein 60 (hsp60) induces cultured epithelial cell proliferation within 24 h. The number of viable cells in hsp60-treated culture was 37% higher than the number in the control at 24 h but 27% lower at 144 h. A kinetics study of the effect of hsp60 on the phosphorylation of mitogen-activated protein kinases (MAPKs) involving Western blotting with phospho-specific antibodies showed that in addition to a transient early increase in p38 levels, a second peak appeared in keratinocytes 24 h after the addition of hsp60. In contrast, prolonged incubation with hsp60 caused a decrease in the level of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) compared with that in the controls, possibly as a result of protein phosphatase activity (Zhang, Pelech; Uitto, 2004).26

In a study for detecting the presence of periopathogenic bacteria in persistent periapical lesions and to compare the reliability of two different methods: anaerobic culture and the DNA hybridization technique was verified that in at least one periodontal pathogenic bacterium was found in seven of 24 cases. Bacterial species present were Treponema denticola (three cases), Porphyromonas gingivalis (three cases), Tannerella forsythensis (four cases), Prevotella intermedia (one case), and Actinobacillus actinomycetemcomitans (three cases) (Lin; Sela; Sprecher, 2007).27 Against these bacteria are also express gene-encoded molecules named of antimicrobial peptides, firstly discovered for their microbicidal properties, but that recently shown to have pro- or anti-inflammatory functions. Their role as immune regulators is being expanded with evidence that some antimicrobial peptides stimulate epithelial migration, proliferation and cytokine or chemokine production. Schauber J, Gallo RL, 2007).28 hBD-2, -3, and -4 but not hBD-1 stimulated human keratinocytes to increase their gene expression and protein production of IL-6, IL-10, IP-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-3alpha, and RANTES. This stimulatory effect was markedly suppressed by pertussis toxin and U-73122, inhibitors for G protein and phospholipase C, respectively. Was also demonstrated that hBDs elicited intracellular Ca2+ mobilization, and increased keratinocyte migration, and proliferation. In addition, these peptides induced phosphorylation of EGFR, signal transducer and activator of transcription (STAT)1, and STAT3, which are intracellular signaling molecules involved in keratinocyte migration and proliferation (Niyonsaba; Ushio; Nakano; Sayama; et al., 2007).29

In the epithelial rests of Malassez, in vitro, was detected the mRNA expression of interleukin (IL)-1 alpha, IL-6, IL-8, and granulocyte macrophage colony-stimulating factor (GM-CSF), and beta defensin 1 (BD-1) - an antimicrobial peptide - having been also studied the effect of lipopolysaccharide (LPS) on the mRNA expression by quantitative RT-PCR assay with a LightCycler, using the double-stranded DNA dye SYBR Green I. The mRNA expressions of IL-1 alpha, IL-6, IL-8, and GM-CSF were upregulated by stimulation with LPS in a dose- and time-dependent manner. Epithelial cells incubated with 1000 ng/ml of LPS for 6 h showed the most significant upregulation of the cytokine mRNAs. On the other hand, no obvious alteration of BD-1 expression by LPS stimulation was observed (Liu F, Abiko Y, Nishimura M, Kusano K, Shi S, Kaku T, 2001).30

Histological investigations have demonstrated that root canal sealers can induce from mild to severe inflammatory alternations, causing deregulated cytokine productions at local disease sites. Of these, Interleukin (IL)-6 and IL-8 released have been reported to play an important role in the pathogenesis of inflammation, considering that the exposure of quiescent U2OS cells to N2 and AH Plus resulted in the induction of IL-6 and IL-8 mRNA gene expression (p < 0.05). The intensity of IL-8 mRNA gene was found to be significant higher than IL-6 mRNA gene (p < 0.05) suggesting that this expression might be one of the pathogenesis of zinc oxide-eugenol based and epoxy resin based root canal sealers-induced periapical inflammation (Huang FM, Tsai CH, Yang SF, Chang YC 2005),31 stimulating the proliferation of epithelial rest of Malassez.

Using immunohistochemistry, confocal and light microscopy, Malassez epithelium and gingival epithelium from mature cats (n = 5) were examined for cells containing the neuropeptides calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP) having been verified that Malassez epithelium regularly displayed cells immunoreactive to CGRP, SP, and VIP, most frequently present in the epithelial cell clusters and inside strands of Malassez located in the cervical half of thc periodontal ligament, suggesting that the presence of neuroendocrine cells in Malassez epithelium strongly would imply in biological functions of this tissue, and the neuropeptide content might, thus, to indicate endocrine functions of the cells (Kvinnsland; Tadokoro; Heyeraas; Kozawa et al., 2000),32 modulating their cellular proliferation via RANKL, considering that epithelial rests of Malassez present immunoreactivity of TrkA, which is an high-affinity receptor of nerve growth factor (NGF), in the periodontal ligament of rats (Yamashiro; Fujiyama; Fukunaga; Wang et al., 2000).33

Hedgehog family (Hh) of intercellular signaling proteins have come to be recognized as key mediators of many fundamental processes in embryonic development. In some contexts, Hedgehog signals act as morphogens in the dose-dependent induction of distinct cell fates within a target field, in others as mitogens regulating cell proliferation or as inducing factors controlling the form of a developing organ (Ingham PW, McMahon AP, 2001).34 In most mouse keratocysts arised from quiescent rests of Malassez, was demonstrated that epithelium-specific Hh signaling might reprogram these cells to proliferate, stratify, and terminally differentiate. Moreover, analysis of early keratocysts in K5-Gli2 mice reveals that these lesions originate by reactivation of quiescent epithelial rests of Malassez, triggering proliferation, stratification, and terminal differentiation of these normally quiescent cells, resultant of the combined function of Hh-regulated Gli transcription factors (Gli1, Gli2, and Gli3) controls Hh-mediated alterations in gene expression in responsive types cellular (Grachtchouk; Liu; Wang; Wei et al., 2006).35

So, we hypnotize that in the evolution from periapical granuloma to cyst implicates in a state of continue hypersensibility immune, culminating with the proliferation epithelial rest of Malassez partially induced by activation of nitric oxide synthase (NOS) via activation of guanylate cyclase (sGC) by NO, resulting in the production intracellular of cGMPc, able to activate Hedgehog family of intercellular signaling proteins, inducing the Gli2-mediated reactivation of quiescent epithelial rests and their differentiation into cystic lining cell as well as their proliferation epithelial, also via PGE2 effects resultant of the selective stimulation of the EP2 receptor subtype mediated by ERK1/2 activation, leading to epidermal growth factor receptor (EGFR) transactivation via protein kinase A (PKA) and c-Src activation. In addition, decrease in cyclin D1 levels induced by NO arrests epithelial cells in the G1 phase. However, noxin, identified as a nitric oxide (NO)-inducible gene, p53/p21(cip1/waf1) and p53 independent cyclin D1 pathways might be also involved, causing induction of apoptosis of the central cells in proliferates epithelial rests of Malassez and formation of cystic cavity, contributes too, at least in part, to their long period of ‘dormancy” or “quiescence” while the proliferate stimuli is not preponderant. In these process, salient themselves the decreased number of macrophages and CD8+ (citotoxic cells) with localization intra-epithelial attracted to this local by bacterial antigen.

Cytokines and growth factors pro-inflammatory (VEGF/VPF, FGF, IGF, EGF, IL-6, TGF-b1) synthesized and secreted in the periapical region also present proprieties modulators of the immune response and participate of control of the process of proliferation of epithelial rests of Malassez, whose mechanisms, at least in part, cause alteration in the normal expression of keratins , via activation of AP-1 target genes (k5, k8, k14 k18 and k19) involved in the control of the cell proliferation including cyclin D1 and PCNA.

In the process of hypersensibility immune, especially cellular and mediated for antibodies, salient itself the participation of lymphocytes and macrophages, as well as mast cells able to product metalloproteinases and other proteinases inductors of the synthesis and secretion of chemistries mediators, such as nitric oxide (NO), promoter of the inhibition of the synthesis and secretion of cytokines and chemokines (IP-10) inhibitors of the epithelial proliferation; or as urokinase plasminogen activator (uPA), also directly involved in the epithelial cellular proliferation.

Of these metalloproteinases, protrude itself the participation of MMP-13, expressed in fibroblast, epithelial cell and endothelial cells, as resultant of their interaction with immune cells, which conjunctly with VIP, is able to interact with ON, especially synthesized and secreted by macrophages. Eosinophils have also participation in the process of epithelial proliferation by to synthesize and to secrete TGF-beta 1, altering the kinetic of the cellular cycle, as result of the production of cellular and nuclear factors, including the absence or disruption of cyclin-dependent kinase inhibitors; therefore, actuating as epithelial growth-promoting factor.

Bacterial antigens of the intracanal microbiota, and that eventually may be identified in the interior of the granulomatous tissue, among other, from Actinobacillus actinomycetemcomitans, Treponema denticola Porphyromonas gingivalis and Prevotella intermedia, such as of the family of Heat shock protein 27, 60, 70 (hsp27, 60, 70) have also participation in the final phase of evolution from granuloma to cyst, because are able to promote the epithelial proliferation and to contribute to formation of the cavity cystic, via biphasic activation of MAPKs ERK1/2 and P38, involving a short-term activator effect for ERK1/2 resulting in increased cell proliferation, as well as a long-term effect, however, resulting in a sustained phosphorylation of p38 and an increased rate of cell death, contributing to formation of the cavity cystic in the proliferant rest.

In addition, is possible that antimicrobial peptides human or beta-defensins (hBD) and LL-37 expresses in epithelial rest of Malassez activate different immune and inflammatory cells, against these bacterias, inducing phosphorylation of EGFR, signal transducer and activator of transcription (STAT)1, and STAT3, which are intracellular signaling molecules involved in epithelial proliferation.

In epithelial periapical lesions and resistant to the endodontic treatment, these antigens together with antigens promoted by root canal sellers are able to induce to synthesis and secretion of several cytokines, such as IL-6, which induces the cell cycle to arrest at G1/S phase, also inducing cellular proliferation in Malassez rests. This cytokine, conjunctly with other cytokines and chemokines (IL8, MCP-1, RANTES, SP) are also able to promote the proliferation of these rests for activating RANKL receptors express in epithelial cells, possibly via a linear signaling cascade: RANKL → RANK → IKKα → IκBα → NF-κB → cyclin D1. In addition, other cytokines and growth involved in the attempt of repair of the periapical region of the endodontic treated tooth also induces epithelial proliferation of these lesions.

Therefore, we postulate that in epithelial granulomas resistant to the endodontic treatment, the epithelial proliferation is caused for the production of cytokines and growth factors involved in the attempt of bone repair. In lesions without treatment, the evolution from granuloma to cyst is caused for the hyperactivation of the immune response resulting in the augment of the production of nitric oxide, principally, for macrophages and CD8+ (citotoxic) cells, with diminution of the production of some cytokines and growth factors pro-inflammatory to a level a little superior the physiologic, without to cause suppression of immune response via CD8+ (suppressor) cells, such as affirmed Rondini and Lara (2001), as well as inducing the activation of genes activators of the cellular proliferation as via these mediators as directly by nitric oxide,.



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