The Role of TNF-α as a Proinflammatory Cytokine in Pathological Processes
Luciano B. Silva1, Alexandrino P. dos Santos Neto2, *, Sandra M.A.S. Maia1, Carolina dos Santos Guimarães1, Iliana L. Quidute1, Alessandra de A.T. Carvalho2, Severino A. Júnior3, Jair C. Leão2
1 Departament of Endodontics, University of Pernambuco (UPE), 1650 Gal Ne wton Cavalcanti Avenue, Camaragibe, PE, Brazil 54753-020
2 Department of Clinical and Preventive Dentistry, Health Sciences Center, Federal University of Pernambuco (UFPE), 1235 Prof. Moraes Rego Street, Recife, PE, Brasil 50670901
3 Department of Fundamental Chemistry, Exact and Nature Sciences Center, Federal University of Pernambuco (UFPE), Prof. Luis Freire Street, Recife, PE, Brasil 50740-540
TNF-α is a member of the vast cytokine family being considered a proinflammatory substance produced many by macrophages and other cells belonging to the innate immunity, many of them classified as indeed Antigen Presenting Cells (APCs) involved in the complex chemotactic process of activation of the adaptive immunity. The aim of this work was to accomplish a literature review concerning the main pathologies that have TNF-α as a modulating agent in other to bring light to the main interactions present in the inflammation installed.
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* Address correspondence to this author at Department of Clinical and Preventive Dentistry, Health Sciences Center, Federal University of Pernambuco (UFPE), 1235 Prof. Moraes Rego Street, Recife, PE, Brasil, 50670901, Tel: +55-81-21268818; Fax: +55-81-21268818; E-mail: firstname.lastname@example.org
The Role of TNF-α as a Proinflammatory Cytokine in Pathological Processes
Cytokines are classified as a category of small proteins (~5–20 kDa) essential for cell signaling; modulating the complex functions of the immunologic system by either enhancing or inhibiting the behavior of other nearby or distant cells, Cytokine gene expression: part of host defence in pulpitis [1Zehnder M, Delaleu N, Du Y, Bickel M. Cytokine gene expression: Part of host defence in pulpitis. Cytokine 2003; 22(3-4): 84-8. [http://dx.doi.org/10.1016/S1043-4666(03)00116-9] [PMID: 1284 9707] ]. This family of substances is vast, and the way they act in vivo still challenge scientists. Their most studied members are the Interleukins (IL), Interferon (IFN), Growth Factor (GF), Coloning-stimulating Factor (CSF), Chemokines (CKs), and Tumor Necrosis Factor (TNF) [2Silva L. A literature review of inflammation and its relationship with the oral cavity. Glob J Infect Dis Clin Res 2015; 1(2): 021-7. [http://dx.doi.org/10.17352/2455-5363.000006] ]. Tumor Necrosis Factor alpha (TNF-α) has been studied for years and exhaustedly described in the scientific literature [3Zhang P, Wu X, Li G, et al. Tumor necrosis factor-alpha gene polymorphisms and susceptibility to ischemic heart disease: A systematic review and meta-analysis. Medicine (Baltimore) 2017; 96(14)e6569 [http://dx.doi.org/10.1097/MD.0000000000006569] [PMID: 2838 3437] ]. It is regarded as a proinflammatory substance produced mainly by macrophages and other cells belonging to the innate immunity, many of them classified as Antigen Presenting Cells (APCs) involved in the chemotactic process of activation of the adaptive immunity in association with interleukins, especially IL-1α, IL-1 β, IL-6 and IL-8 (1), integrating the innate and adaptive immunities [4Alam R, Gorska M. Lymphocytes In: Allergy and Clinic. Immunol 2003; 111(2): 5687-701.].
Many studies have described the role of TNF-α in infectious diseases, as well as in chronic and acute inflammations [5Trowbridge HO, Emling RC. Inflammation. A Review of the Process (5th ed). Quintessence Publishing 200. 1997.]. It was firstly identified in the serum from
mice following administration of bacterial endotoxins, which resulted in cytotoxic or cytostatic effects to human cells, leading to hemorrhagic necrosis, and performing, in experiments with mice, carcinogenic cell regression [6Pennica D, Nedwin GE, Hayflick JS, et al. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature 1984; 312(5996): 724-9. [http://dx.doi.org/10.1038/312724a0] [PMID: 6392892] ].
The excessive production of pro-inflammatory cytokines, which is observed in inflammatory conditions, not only increases the immune response of the host organism, but also causes deleterious effects that are able to modulate hemodynamic regulation and metabolic control [7Reid CL, Perrey C, Pravica V, Hutchinson IV, Campbell IT. Genetic variation in dysfunction syndrome. Crit Care Med 2002; 30(10): 2216-21. [http://dx.doi.org/10.1097/00003246-200210000-00007] [PMID: 1239 4947] ]. Therefore, it is only expectable that different pathologies have, in common, the influence of TNF-α in the course of their establishment and development. Therefore, the aim of this work was to accomplish a literature review concerning the main pathologies that have been described in the literature concerning TNF-α as a modulating agent.
2. LITERATURE REVIEW
Tissues of the immune system are formed by the lymphoid organs, also called primary or central tissues, within which T and B lymphocytes mature, becoming competent cells to respond to the antigens; and peripheral (or secondary) lymphoid organs, where secondary immunological responses to the aggressor agents get started [8Schröder JM. Chemoattractants as mediators of neutrophilic tissue recruitment. Clin Dermatol 2000; 18(3): 245-63. [http://dx.doi.org/10.1016/S0738-081X(99)00117-0] [PMID: 1085 6658] ].
The appropriate immune response depends on the balanced cell-to-cell communication, and also on the overall conditions of the host organisms, including nutrition, environmental matters, as well as genetic programming. Cell recruitment and arrival on the inflamed sites is partially obtained by the synchronized synthesis and function of cytokines and their action on their counterparts: The receptors located mainly on the cell membrane; without which they would never respond. In fact, cytokines define the subpopulation that will be recruited in each step of the immune response, stimulating recruitment or inhibiting production and release [9Cardon LR, Bell JI. Association study designs for complex diseases. Nat Rev Genet 2001; 2(2): 91-9. [http://dx.doi.org/10.1038/35052543] [PMID: 11253062] ].
2.1. Tumor Necrosis Factor Alpha Receptors
TNF-α is produced as a pro-hormone substance constituting 233 amino acids. It is closely linked in the cell membrane of many cell types, and then processed to a 157 residue mature protein by cleavage of a 76 residue signal peptide. Not until 1975 was TNF-α identified as a soluble factor that caused necrosis of tumors, and thereafter came its designation [10Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 1975; 72(9): 3666-70. [http://dx.doi.org/10.1073/pnas.72.9.3666] [PMID: 1103152] ]. It had initially been referred to as Cachectin or Differentiation Inducing Factor (DIF), with two bioactive forms: transmembrane TNF-α (tmTNF-α) and soluble TNF-α (sTNF-α) [11Aggarwal BB. Tumour necrosis factors receptor associated signalling molecules and their role in activation of apoptosis, JNK and NF-kappaB. Ann Rheum Dis 2000; 59(Suppl. 1): i6-i16. [http://dx.doi.org/10.1136/ard.59.suppl_1.i6] [PMID: 11053079] -14Hu X, Li B, Li X, et al. Transmembrane TNF-α promotes suppressive activities of myeloid-derived suppressor cells via TNFR2. J Immunol 2014; 192(3): 1320-31. [http://dx.doi.org/10.4049/jimmunol.1203195] [PMID: 24379122] ]. The latter seem to be able to bind the ligand and inhibit the cytotoxic activities of TNF-α [15Seckinger P, Isaaz S, Dayer JM. A human inhibitor of tumor necrosis factor alpha. J Exp Med 1988; 167(4): 1511-6. [http://dx.doi.org/10.1084/jem.167.4.1511] [PMID: 2833558] ].
Both receptors are in fact proteins. Their extracellular portions link to TNF-α, constituting a receptor family with four characteristic domains with cystine residues regularly spaced [16Dembic Z, Loetscher H, Gubler U, et al. Two human TNF receptors have similar extracellular, but distinct intracellular, domain sequences. Cytokine 1990; 2(4): 231-7. [http://dx.doi.org/10.1016/1043-4666(90)90022-L] [PMID: 1966549] ]. Their proteins seem to be residual fragments of the extracellular regions of the type 1 and type 2 membrane-bound receptors for TNF alpha [17Engelmann H, Novick D, Wallach D. Two tumor necrosis factor-binding proteins purified from human urine. Evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors. J Biol Chem 1990; 265(3): 1531-6. [PMID: 2153136] ].
Later on, the encoding genes of cachectin and TNF-α were confirmed as identical molecules with no need for different meanings (4- Caput, 1986). Once produced and released into the blood stream, TNF-α bind to its two main receptors namely: TNF receptor 1 (TNF-R1), (55-kDa) and receptor 2 (TNF-R2), (75-kDa) [18Hsu H, Shu HB, Pan MG, Goeddel DV. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 1996; 84: 299-308.], distinct from each other, but expressed in many different cell lineage surfaces. R1, corresponds to the majority of the TNF-α activities, being a ubiquitous membrane receptor found in most cell types which rapidly attaches to TNF-α. Receptor 2, on the other hand, is initially expressed intensively by T cells and endothelial cells, for rapid and efficient response by recruiting or inhibiting specific cell types when necessary, such as lymphocytes and clastic lineages [19Schall TJ, Lewis M, Koller KJ, et al. Molecular cloning and expression of a receptor for human tumor necrosis factor. Cell 1990; 61(2): 361-70. [http://dx.doi.org/10.1016/0092-8674(90)90816-W] [PMID: 2158863] -21Santee SM, Owen-Schaub LB. Human tumor necrosis factor receptor p75/80 (CD120b) gene structure and promoter characterization. J Biol Chem 1996; 271(35): 21151-9. [http://dx.doi.org/10.1074/jbc.271.35.21151] [PMID: 8702885] ]. The former is activated by either sTNF-α or tmTNF-α; while the latter is preferentially activated by tmTNF-α [22Turner SJ, La Gruta NL, Stambas J, Diaz G, Doherty PC. Differential tumor necrosis factor receptor 2-mediated editing of virus-specific CD8+ effector T cells. Proc Natl Acad Sci USA 2004; 101(10): 3545-50. [http://dx.doi.org/10.1073/pnas.0307347101] [PMID: 14993609] , 23Kim EY, Teh HS. Critical role of TNF receptor type-2 (p75) as a costimulator for IL-2 induction and T cell survival: A functional link to CD28. J Immunol 2004; 173(7): 4500-9. [http://dx.doi.org/10.4049/jimmunol.173.7.4500] [PMID: 15383581] ]. Sometimes, however, a small degree of overlap and cross talk between both receptors may occur, despite being structurally different. The stimulation, however, does not seem to be altered. Anyway, the binding of TNF-α to receptor 1 may activate the transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells, regulating cytokine production, and modulating inflammation and apoptosis, depending on the immunological need [24Bouwmeester T, Bauch A, Ruffner H, et al. A physical and functional map of the human TNF-α/NF-kappa B signal transduction pathway. Nat Cell Biol 2004; 6(2): 97-105. [http://dx.doi.org/10.1038/ncb1086] [PMID: 14743216] ].
Protein Kinases (PTKs) are enzymes that regulate the biological activity of proteins by phosphorylation of specific amino acids with ATP as the source of phosphate, thereby inducing a conformational change from an inactive to an active protein. Although TNF-α receptors do not have activity of intrinsic protein kinase, they respond very quickly to TNF-α stimulation, causing phosphorylation of several distinct proteins [25Vilcek J, Lee TH. Tumor necrosis factor. New insights into the molecular mechanisms of its multiple actions. J Biol Chem 1991; 266(12): 7313-6. [PMID: 1850405] ].
2.2. Tumor Necrosis Factor Alpha Association with Interleukins
The interaction between the cytokine family members are necessary steps for the establishment and development of inflammation, simply because of the amplification of the responses produced by each of their kinds. In this context, TNF-α is usually produced simultaneously with interleukins potentializing pro-inflammatory vascular and cellular alterations [26Meyer O. Role of TNF-α lpha and cytokines in the physiopathology of rheumatoid arthritis. Therapeutic perspectives. Bull Acad Natl Med 2003; 187935954]. Therefore, TNF-α and IL-1 are usually produced together as a prompt response to bacterial infections. Together they both modulate pro-inflammatory signals by coordinating vascular and cellular changes in the immune system, activating many of the components present in the innate immunity, increasing the expression of chemokines and adhesion molecules, critical for the recruitment of neutrophils from the blood, initiating the immune first lineage prompt response in the host [27Bazzoni F, Beutler B. The tumor necrosis factor ligand and receptor families. N Engl J Med 1996; 334(26): 1717-25. [http://dx.doi.org/10.1056/NEJM199606273342607] [PMID: 8637 518] -29Mehrad B, Standiford TJ. Role of cytokines in pulmonary antimicrobial host defense. Immunol Res 1999; 20(1): 15-27. [http://dx.doi.org/10.1007/BF02786504] [PMID: 10467980] ].
TNF-α biological main effect tends to integrate both innate and adaptive immunities, although this designation is merely didactical, due to the reciprocal bioactivation of both sort of immunities, which clinically means that they are so interacted that could not be studied as separate matters [30Chaplin DD. Overview of the immune response. J Allergy Clin Immunol 2010; 125(2)(Suppl. 2): S3-S23. [http://dx.doi.org/10.1016/j.jaci.2009.12.980] [PMID: 20176265] ]. Initially, TNF-α potentializes T and B leukocytes activation, which also affects via feedback chemotaxis, macrophages and Natural Killer (NK) cells, both Antigen Presenting Cells (APC) belonging to the innate immunity. Such cell-to-cell interaction leads to a cascade of events, also stimulating the adaptive immunity to interact, which is represented mainly by T and B lymphocytes, responsible for antibody production [31Boyce BF, Li P, Yao Z, et al. TNF-α and pathologic bone resorption. Keio J Med 2005; 54(3): 127-31. [http://dx.doi.org/10.2302/kjm.54.127] [PMID: 16237274] ]. TNF-α also triggers Prostaglandins (PG) production, increasing fever induction, and the release of the acute inflammation phase proteins, such as C-Reactive Protein (CRP), gene expression of cytokines and chemokines, and endothelial cell activation [8Schröder JM. Chemoattractants as mediators of neutrophilic tissue recruitment. Clin Dermatol 2000; 18(3): 245-63. [http://dx.doi.org/10.1016/S0738-081X(99)00117-0] [PMID: 1085 6658] ], contributing significantly to vascular changes for increased blood flow in the site of the injury. Some studies have similarly reassured that TNF-α, in association with other interleukins, potentiate bone resorption capacity [32Prso IB, Kocjan W, Simić H, et al. Tumor necrosis factor-alpha and interleukin 6 in human periapical lesions. Mediators Inflamm 2007; 2007(38210): 38210. [PMID: 17497030] , 33LIGHT. R. J.; PILLEMER, D. B. Summing up: The science of reviewing research.HIGGINS, J P T; GREEN, S Cochrane Handbook for Systematic Reviews and Interventions 425 Capítulo 8 2005. [http://dx.doi.org/10.1155/2007/38210] ].
2.3. Tumor Necrosis Factor Alpha and Genetic Polymorphisms
The gene that encodes TNF-α is located in the short arm of chromosome 6, in the 6p21.3 region. Single Nucleotide Polymorphisms (SNPs) are the most common variation in the human genome that differentiate from the rare mutations because they present frequency of at least 1% of the less common allele in the population. One SNP takes place in virtually 1 out of a thousand base pairs and their most common replacement (2/3 of the overall) is of one cytosine by a tymine (C/T) [34Brookes AJ. The essence of SNPs. Gene 1999; 234(2): 177-86. [http://dx.doi.org/10.1016/S0378-1119(99)00219-X] [PMID: 1039 5891] , 35Arcaroli J, Fessler MB, Abraham E. Genetic polymorphisms and sepsis. Shock 2005; 24(4): 300-12. [http://dx.doi.org/10.1097/01.shk.0000180621.52058.e1] [PMID: 1620 5313] ]. One SNP may influence the genic product by different manners: (i) variations in un-translated region 5’ (5’UTR - 5’ Un-translated Region) may modify the mRNA translation; (ii) variation in un-translated region 3’ (3’UTR - 3) may affect the clivage, stability and the transport of mRNA, thus altering protein productions which clinically may imply in differentiated cell functions, for better or for worse.
SNPs may occur in the coding region, or in the regulatory region of the gene, leading to changes in the amino acid sequence of the encoded protein, or its production rate. For being bi-allelic, SNPs can be detected by using techniques that discriminate any different combinations in the nucleotides Adenine (A), Thymine (T), Cytokine (C) and Guanine (G). Among the SNPs, the -308 G/A (rs1800629) in the promoter region is described as being able to increase the gene expression and therefore the level of TNF-α production due to the transition from wild-type G allele to the variant A allele [36Qidwai T, Khan F. Tumour necrosis factor gene polymorphism and disease prevalence. Scand J Immunol 2011; 74(6): 522-47. [http://dx.doi.org/10.1111/j.1365-3083.2011.02602.x] [PMID: 2179 0707] ].
TNF-α is encoded in the promoter region -308 G/A (rs1800629) and admits three different kinds of genetic profiles: The homozygous form G/G, and the mutant variant forms G/A and A/A. The wild type genetic profile G/G is most commonly found in a specific population studied, usually associated with low level TNF-α-producing individuals. The mutant form, G/A, on the other hand, is related to intermediate production, while the rarer form, A/A, is associated with high level TNF-α- producing individuals. Expectable as it seems, it is possible to speculate that the presence of such genetic polymorphisms could exacerbate the inflammatory responses depending of the genetic individual profile, modulating the course of the disease, and therefore the immune response of the organism [37MORSANI J. M. Genetic predisposition to persistent apical periodontitis. J Endod 2011; 37(4): 455-9.]. Pathologies such as pulpitis and periodontitis have recently been investigated as for the changes in inflammatory intensity due to the genetic profile. Table 1 exemplifies the effects of the genotypes in the inflammatory response.
Table 1 Effects of the genetic profile on the inflammatory response.
2.4. Tumor Necrosis Factor Alpha and Periapical Lesions
The two most common lesion types in the periapical area are granulomas and periapical cysts [38Morse DR, Patnik JW, Schacterle GR. Electrophoretic differentiation of radicular cysts and granulomas. Oral Surg Oral Med Oral Pathol 1973; 35(2): 249-64. [http://dx.doi.org/10.1016/0030-4220(73)90292-2] [PMID: 4513070] -40Lin LM, Huang GT, Rosenberg PAJ. Proliferation of epithelial cell rests, formation of apical cysts, and regression of apical cysts after periapical wound healing. J Endod 2007; 33(8): 908-16. [http://dx.doi.org/10.1016/j.joen.2007.02.006] [PMID: 17878074] ]. Both lesions are usually expansible, and their establishment costs to the organism more than just bone resorption, but also the differentiation, recruitment and arrival of different cell types on the injury site, depending on the inflammatory phase inflicted by them.
The origin of the periapical lesions is associated with bacterial contamination and posterior necrosis of the dental pulp. The progress of this process usually goes through four well determined stages: a) exposure of the dental pulp to the oral cavity; b) subsequent penetration and bacterial colonization; c) pulp inflammation and finally; d) necrosis. The inflammatory response involves leukocyte-activation, initially neutrophils from innate immunity, which will chemotactically recruit and signalize more sophisticated leukocytes from the adaptive immunities [41Del Rey A, Besedovsky H, Sorkin E, Dinarello CA. Interleukin-1 and glucocorticoid hormones integrate an immunoregulatory feedback circuit. Ann N Y Acad Sci 1987; 496: 85-90. [http://dx.doi.org/10.1111/j.1749-6632.1987.tb35749.x] [PMID: 3037 979] -43Galbraith GMP, Steed RB, Sanders JJ, Pandey JP. Tumor necrosis factor alpha production by oral leukocytes: influence of tumor necrosis factor genotype. J Periodontol 1998; 69(4): 428-33. [http://dx.doi.org/10.1902/jop.19184.108.40.2068] [PMID: 9609372] ], resulting in osteoclastogenesis and the formation of osteolytic lesion around the dental apex, easily observed in routine periapical radiographs, especially in long term chronic lesions [44Ricucci D, Siqueira JF Jr, Bate AL, Pitt Ford TR. Histologic investigation of root canal-treated teeth with apical periodontitis: A retrospective study from twenty-four patients. J Endod 2009; 35(4): 493-502. [http://dx.doi.org/10.1016/j.joen.2008.12.014] [PMID: 19345793] , 45Nair PN. Pathogenesis of apical periodontitis and the causes of endodontic failures. Crit Rev Oral Biol Med 2004; 15(6): 348-81. [http://dx.doi.org/10.1177/154411130401500604] [PMID: 15574679] ], leading to bone resorption, for which there is no expectation of neoformation or cure without endodontic therapy [46Liapatas S, Nakou M, Rontogianni D. Inflammatory infiltrate of chronic periradicular lesions: An immunohistochemical study. Int Endod J 2003; 36(7): 464-71. [http://dx.doi.org/10.1046/j.1365-2591.2003.00627.x] [PMID: 1282 3701] ].
The very nature of the periapical lesions results, most of the times, in bone resorption, observed by the local production of PGE2, IL1-β, and TNF-α [47Kabashima H, Nagata K, Maeda K, Iijima T. Involvement of substance P, mast cells, TNF-α and ICAM-1 in the infiltration of inflammatory cells in human periapical granulomas. J Oral Pathol Med 2002; 31(3): 175-80. [http://dx.doi.org/10.1034/j.1600-0714.2002.310309.x] [PMID: 1190 3825] ]. The interaction of prostaglandins, interleukins and TNF-α seems to be potent enough to cause fast bone destruction in the periapex, as well as granulomatous tissue formation, which are typical features of the periapical lesions [48Delima AJ, Oates T, Assuma R, et al. Soluble antagonists to Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) inhibits loss of tissue attachment in experimental periodontitis. J Clin Periodontol 2001; 28(3): 233-40. [http://dx.doi.org/10.1034/j.1600-051x.2001.028003233.x] [PMID: 11 284536] ].
3. TUMOR NECROSIS FACTOR ALPHA AND CARDIAC INJURIES
Not until 1990 was TNF-α recognized as a participant in congestive heart failure (CHF), when it was demonstrated that its high circulating seric levels were linked with the final stage of heart failure [49Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323(4): 236-41. [http://dx.doi.org/10.1056/NEJM199007263230405] [PMID: 21953 40] ].
Heart failure is in general related to myocyte damage with prior injury history. The main responsible are habits such as Alcohol, smoking and sedentarism, factors that increase cardiac failure risk. Hearts in normal conditions do not express the TNF-α protein or its transcripts. On the other hand, failing hearts do express TNF-α not only because of chemical mediators unleashed by blocked vessels, but also because of reduced contractibility of the myocytes in its presence. The elevation of plasmatic seric levels of cytokines acting as pro-inflamatory mediators during and after myocarditis and infarction corroborates in this sense [50Matsumori A, Yamada T, Suzuki H, Matoba Y, Sasayama S. Increased circulating cytokines in patients with myocarditis and cardiomyopathy. Br Heart J 1994; 72(6): 561-6. [http://dx.doi.org/10.1136/hrt.72.6.561] [PMID: 7857740] ].
A series of seminal studies demonstrated that normal human hearts did not express TNF-α protein or transcripts, whereas end-stage failing hearts expressed TNF-α as assessed by Enzyme-Linked Immunosorbent Assay (ELISA), Northern blot, and immunohistochemistry [51Torre-Amione G, Kapadia S, Lee J, et al. Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation 1996; 93(4): 704-11. [http://dx.doi.org/10.1161/01.CIR.93.4.704] [PMID: 8640999] ]. The process is complex and involves interactions of interleukins and chemokines, and in many situations, the real cause remains unclear, which made researchers investigate the role of cytokines in the process. It is clinically known that failing hearts do have some degree of inflammatory cell infiltrates, a fact that can be expected as a source of TNF-α, in cardiac myocytes and nonmyocytes [52Badorff C, Noutsias M, Kühl U, Schultheiss HP. Cell-mediated cytotoxicity in hearts with dilated cardiomyopathy: Correlation with interstitial fibrosis and foci of activated T lymphocytes. J Am Coll Cardiol 1997; 29(2): 429-34. [http://dx.doi.org/10.1016/S0735-1097(96)00475-5] [PMID: 9015000] , 53Habib FM, Springall DR, Davies GJ, Oakley CM, Yacoub MH, Polak JM. Tumour necrosis factor and inducible nitric oxide synthase in dilated cardiomyopathy. Lancet 1996; 347(9009): 1151-5. [http://dx.doi.org/10.1016/S0140-6736(96)90610-8] [PMID: 8609750] ]. The three most commonly involved cytokines concerning heart failures are TNF-α, IL-1, and IL-6. With synergic interactions, they are all capable of amplifying the inflammatory response of preexistent cardiac alterations, especially those that obliterate blood vessels. Bacterial endotoxin Lipopolysaccharide (LPS) has been related as one of the most powerful TNF-α inducers, even with very small circulating amounts.
In a study conducted with hamsters, TNF-α inhibited the contractility of isolated papillary muscles, in a concentration-dependent and reversible manner [54Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992; 257(5068): 387-9. [http://dx.doi.org/10.1126/science.1631560] [PMID: 1631560] ]. Later on it was suggested that the individual susceptibility of myocardium infarction could be related to genetic factors. From that point on, researchers began studying the influence of individual genetic profiles in the development of cardiac failures.
There have been growing evidence that the G/A polymorphism in the -308 promoter region of the TNF-α gene may affect the transcription, expression, and the consequent biological activity of TNF-α, indicating that the individual genetic profile may play a determinant role in its clinical behavior [55Chang WT, Wang YC, Chen CC, et al. The -308G/A of Tumor Necrosis Factor (TNF)-α and 825C/T of Guanidine Nucleotide Binding Protein 3 (GNB3) are associated with the onset of acute myocardial infarction and obesity in Taiwan. Int J Mol Sci 2012; 13(2): 1846-57. [http://dx.doi.org/10.3390/ijms13021846] [PMID: 22408428] ]. A study [56Antonicelli R, Olivieri F, Cavallone L, et al. Tumor necrosis factor-alpha gene -308G > A polymorphism is associated with ST-elevation myocardial infarction and with high plasma levels of biochemical ischemia markers. Coron Artery Dis 2005; 16(8): 489-93. [http://dx.doi.org/10.1097/00019501-200512000-00006] [PMID: 1631 9659] ] concluded that Italians with the mutant gene (A) polymorphism, high producing (A/A) and intermediate producing genotype (G/A), had a higher risk of ST-segment elevation myocardium infarction than others who did not express polymorphisms. It was also observed that the reperfusion therapy after myocardium infarction has been associated with episodes of ischemia/reperfusion injury or no-reflow, which is related to TNF-α, as well as myocardium stunning and left ventricular systolic dysfunction [57Bolli R, Marbán E. Molecular and cellular mechanisms of myocardial stunning. Physiol Rev 1999; 79(2): 609-34. [http://dx.doi.org/10.1152/physrev.19220.127.116.119] [PMID: 10221990] , 58Dhalla NS, Golfman L, Takeda S, Takeda N, Nagano M. Evidence for the role of oxidative stress in acute ischemic heart disease: A brief review. Can J Cardiol 1999; 15(5): 587-93. [PMID: 10350670] ].
TNF-α does not encounter barriers once it is produced and released; reaching cell receptors wherever blood irrigates. It seems to play a determinant role in cardiac injuries, although its action in most cardiac cell type is still unclear. Anyhow, TNF-α-activated signal transduction pathways have been postulated to act on adverse ventricular remodeling after myocardial infarction, as well as being a major contributor during the development and progression of heart failure [59Ping Z, Aiqun M, Jiwu L, Liang S. TNF receptor 1/2 predict heart failure risk in type 2 diabetes mellitus patients. Int Heart J 2017; 58(2): 245-9. [http://dx.doi.org/10.1536/ihj.16-236] [PMID: 28367848] ].
4. TUMOR NECROSIS FACTOR ALPHA AND ARBOVIRUSES
Arboviruses have also been researched in relation with TNF-α alterations. Increased levels of TNF-α have been associated with Dengue virus (DENV) infection. The main symptoms of DENV infection is dengue hemorrhagic fever/ dengue shock syndrome (DHF/DSS) [60Green S, Rothman A. Immunopathological mechanisms in dengue and dengue hemorrhagic fever. Curr Opin Infect Dis 2006; 19(5): 429-36. [http://dx.doi.org/10.1097/01.qco.0000244047.31135.fa] [PMID: 1694 0865] ]. It is known that TNF-α affects the vascular Endothelial Cells (EC), as well as endothelial leukocyte interactions, promoting disruption of cell-cell junctions, disassembly of focal adhesion complexes, and morphological changes leading to increased vascular permeability [61Tracey KJ, Cerami A. Tumor necrosis factor, other cytokines and disease. Annu Rev Cell Biol 1993; 9: 317-43. [http://dx.doi.org/10.1146/annurev.cb.09.110193.001533] [PMID: 8280 464] ]. With all of such alterations, this potent cytokine is able to stimulate bleeding, one of the main problems concerning this disease. Seemingly, altered serum levels have also been found in patients bearers of Zika virus [62Kam Y-W, Leite JA, Lum F-M, et al. Zika-Unicamp Network. Specific biomarkers associated with neurological complications and congenital central nervous system abnormalities from Zika virus-infected patients in Brazil. J Infect Dis 2017; 216(2): 172-81. [http://dx.doi.org/10.1093/infdis/jix261] [PMID: 28838147] ].
5. TUMOR NECROSIS FACTOR ALPHA AND ALZHEIMER´S DISEASE
Alzheimer’s Disease (AD) is the main cause of dementia worldwide. It represents one of the most serious and severe health problems for the elderly. There are a number of cytokines involved in the modulation of neuroinflammation, but TNF-α seems to play a pertinent role, particularly in the peripheral and central nervous system of adults, despite the fact that healthy adults do have low levels of it. Serum levels if this cytokine is significantly higher in blood14 and central nervous system [63Tarkowski E, Andreasen N, Tarkowski A, Blennow K. Intrathecal inflammation precedes development of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2003; 74(9): 1200-5. [http://dx.doi.org/10.1136/jnnp.74.9.1200] [PMID: 12933918] ]) of patients with Alheimer diseases, and clinical and animal studies have shown that there seems to be a link between high TNF-α serum levels in the brain and AD [64Cheng X, Shen Y, Li R. Targeting TNF: A therapeutic strategy for Alzheimer’s disease. Drug Discov Today 2014; 19(11): 1822-7. [http://dx.doi.org/10.1016/j.drudis.2014.06.029] [PMID: 24998784] ].
6. TUMOR NECROSIS FACTOR ALPHA AND CANCER
TNF-α is highly involved in patients with cancer, and clinically it can be easily noticed by abnormal amounts of it in the seric levels. Its effect on the tumorous cells seems to be the formation of oxygen radicals inside the cells exposed to it [65Zimmerman RJ, Chan A, Leadon SA. Oxidative damage in murine tumor cells treated in vitro by recombinant human tumor necrosis factor. Cancer Res 1989; 49(7): 1644-8. [PMID: 2924312] ]. It is only natural and expectable that the inflammation caused by the growing tumor, and the chemotactic effects and defects due to it, implicates in cytokine production. Since TNF-α has shown abilities to inhibit tumor growth, its anti-tumour effect in vivo has been hypothesized to be mediated by selective damage to tumour-associated vasculature, by decreasing blood flow [66Jäättelä M. Biologic activities and mechanisms of action of tumor necrosis factor-alpha/cachectin. Lab Invest 1991; 64(6): 724-42. [PMID: 1646350] ], and therefore, the systemic administration of TNF-α began to be applied. However, severe toxicity was reported. It seems that humans tolerate a maximum of 8-10µg kg-1 body weight of systemically administered TNF-α before life-threatening toxicities set in. Tumor regression on the other hand, demands doses of nearly 400 µg kg-1, making it impossible for clinical use [67Blick M, Sherwin SA, Rosenblum M, Gutterman J. Phase I study of recombinant tumor necrosis factor in cancer patients. Cancer Res 1987; 47(11): 2986-9. [PMID: 3567916] -69Hieber U, Heim ME. Tumor necrosis factor for the treatment of malignancies. Oncology 1994; 51(2): 142-53. [http://dx.doi.org/10.1159/000227329] [PMID: 8196898] ].
Still concerning cancer, some studies do reveal that the ectopic expression of TNF-α at the site of malignancy induces strong and long-term tumor regression [70Li YC, Kong LH, Li KS. Inducement effect of recombinant human TNF-α on apoptosis of breast cancer cell line ZR75-1 and Its mechanism. Chin J Cancer 2006; 25(5): 560-5. [PMID: 16687074] , 71Marr RA, Addison CL, Snider D, Muller WJ, Gauldie J, Graham FL. Tumour immunotherapy using an adenoviral vector expressing a membrane-bound mutant of murine TNF alpha. Gene Ther 1997; 4(11): 1181-8. [http://dx.doi.org/10.1038/sj.gt.3300528] [PMID: 9425441] ]. On the other hand, a “dark side” of this cytokine has raised in apparent contradiction to its name. There has been increasing evidence that, especially in middle and old age, TNF-α functions are concerned with the promotion and progression of tumors, rather than with protection and worse still; the evidence includes that TNF-α is involved with proliferation, transformation, angiogenesis, invasion, and metastasis in many types of cancers [72Balkwill F. TNF-α in promotion and progression of cancer. Cancer Metastasis Rev 2006; 25(3): 409-16. [http://dx.doi.org/10.1007/s10555-006-9005-3] [PMID: 16951987] ].
7. TUMOR NECROSIS FACTOR ALPHA AND REUMATOID ARTHRITIS
Rheumatoid Arthritis (RA) has been estimated as the most commonly occurring inflammatory arthritis, affecting approximately 0.5-1.0% of the world population [73Spector TD. Rheumatoid arthritis.Epidemiology of Rheumatic Diseases 1990.] and TNF-α overexpression has likewise been present in its bearers. Some follow up studies in TNF-α transgenics, accomplished in the nineties, have found its over-expression in the absence of active T and B cells in patients with this disease [74Keffer J, Probert L, Cazlaris H, et al. Transgenic mice expressing human tumour necrosis factor: A predictive genetic model of arthritis. EMBO J 1991; 10(13): 4025-31. [http://dx.doi.org/10.1002/j.1460-2075.1991.tb04978.x] [PMID: 1721 867] ]. Later on, they have found that there is no requirement for soluble TNF-α to be present, but that the full expression of arthritis may occur even with a membrane-bound form of it (mTNF-α) [75Georgopoulos S, Plows D, Kollias G. Transmembrane TNF is sufficient to induce localized tissue toxicity and chronic inflammatory arthritis in transgenic mice. J Inflamm 1996; 46(2): 86-97. [PMID: 8734789] ]. In cultures accomplished from synovial cells from bearers of rheumatoid arthritis, the blockage of TNF-α with antibodies reduced the production of IL-1, IL-6, IL-8, and GM-CSF significantly.
8. TUMOR NECROSIS FACTOR ALPHA AND INFLAMMATORY BOWEL DISEASES
Inflammatory Bowel Diseases (IBD) are described in the literature as complex disorders comprised by Crohn’s Disease (CD) as well as Ulcerative Colitis (UC) [76Sanchez-Muñoz F, Dominguez-Lopez A, Yamamoto-Furusho JK. Role of cytokines in inflammatory bowel disease. World J Gastroenterol 2008; 14(27): 4280-8. [http://dx.doi.org/10.3748/wjg.14.4280] [PMID: 18666314] ]. In such pathologies, TNF-α has been pointed as inflict increased immune activations, not to mention the well-known effects of cytokines as whole, such as fever induction, bone resorption, insulin resistance, anemia and are some of the activities related to this pro-inflammatory cytokine [77Parameswaran N, Patial S. Tumor necrosis factor-α signaling in macrophages. Crit Rev Eukaryot Gene Expr 2010; 20(2): 87-103. [http://dx.doi.org/10.1615/CritRevEukarGeneExpr.v20.i2.10] [PMID: 21133840] , 78Van Deventer SJ. Tumour necrosis factor and Crohn’s disease. Gut 1997; 40(4): 443-8. [http://dx.doi.org/10.1136/gut.40.4.443] [PMID: 9176068] ]. IBD approach underwent a major revolution when new classes of monoclonal antibodies, such as anti-tumor necrosis factor TNF-α agents, were described [79Armuzzi A, De Pascalis B, Fedeli P, De Vincentis F, Gasbarrini A. Infliximab in Crohn’s disease: early and long-term treatment. Dig Liver Dis 2008; 40(Suppl. 2): S271-9. [http://dx.doi.org/10.1016/S1590-8658(08)60537-X] [PMID: 1859 9000] -81Colombel JF, Sandborn WJ, Panaccione R, et al. Adalimumab safety in global clinical trials of patients with Crohn’s disease. Inflamm Bowel Dis 2009; 15(9): 1308-19. [http://dx.doi.org/10.1002/ibd.20956] [PMID: 19434735] ]. New drug development focused on TNF-α inhibition has been developed to treat autoimmune affections, such as infliximab and azathioprine, or combination therapy for Crohn’s disease. The blocking of TNF-α has been proved efficient in both induction and maintenance of clinical response and remission of IBD [82Hanauer SB, Feagan BG, Lichtenstein GR, et al. ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: The ACCENT I randomised trial. Lancet 2002; 359(9317): 1541-9. [http://dx.doi.org/10.1016/S0140-6736(02)08512-4] [PMID: 12047 962] -85Rubenstein JH, Chong RY, Cohen RD. Infliximab decreases resource use among patients with Crohn’s disease. J Clin Gastroenterol 2002; 35(2): 151-6. [http://dx.doi.org/10.1097/00004836-200208000-00007] [PMID: 1217 2361] ]. Table 2 exemplifies the main effects on the pathologies mentioned above.
Table 2 Main effects of TNF-α on the pathologies of this paper.
Due to its pro-inflammatory effects, TNF-α is directly involved in most of the inflammatory processes in the mammalian organism. It modulates the course of many pathologies with some contradictory effects, either inhibiting or stimulating inflammatory vascular events mainly. Although its interactions with interleukins has been extensively studied, its most complex interactions, however, need to be more investigated.
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CONFLICT OF INTEREST
The author declares no conflict of interest financial or otherwise.
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