人巨細(xì)胞病毒細(xì)胞因子相關(guān)知識(shí)

1、 384race PogldoweeviewsT om/Volume 64; Numer/Number 5/2013ISSN 0423104XDariusz Kajdaniuk M.D., Ph.D., Department of Pathophysiology and Endocrinology, Medical University of Silesia, Zabrze, Pl. Traugutta 2,41800 Zabrze, Poland, fax: +48 32 271 26 41, e-mail: .plTransforming g

2、rowth factor b1 (TGFb1 in physiology and pathologyTransformujcy czynnik wzrostu b1 (TGFb1 w fizjologii i patologiiDariusz Kajdaniuk1, Bogdan Marek1, Halina Borgiel-Marek2, Beata Kos-Kuda11Department of Pathophysiology and Endocrinology, Medical University of Silesia, Zabrze, Katowice, Poland 2Depart

3、ment and Clinic of Maxillofacial Surgery, Medical University of Silesia, Katowice, PolandAbstractThis review describes precisely the consequence of TGFb1 prevalence in the organism, and its significant influence on physiological and pathophysiological processes. Organ and tissue distinctiveness hind

4、er unambiguous characterisation of the cytokine. However, there are constant functions of TGFb1 inducing no controversy: it participates in foetal development, control of cell growth and differentiation, induces fibrosis and scar formation (the process of wound healing, causes the suppression of imm

5、une response, is involved in angiogen-esis, the development of tumours, and inflammatory processes. Thus, TGFb1 is a multifunctional cytokine. There are three fundamental directions of its activities: I. TGFb1 regulates cell proliferation, growth, differentiation and cells movement. II. TGFb1 has im

6、munomodu-latory effects. III. TGFb1 has profibrogenic effects. TGFb1 action can be local and systemic. This review describes TGFb1 in pathology: colitis ulcerosa, Crohns disease, coeliac disease, diabetic nephropathy, diabetic retinopathy and diabetic foot, pulmonary hypertension, and Alzheimers dis

7、ease. TGFb1 and its receptors are also of interest to endocrinologists. Lack of TGFb1-dependent growth control may result in oncogenesis: papillary, follicular and anaplastic thyroid cancers, prostate, breast and uterine cervical cancer, oesophagus, gastric, colorectal and liver cancers, NSCLC, and

8、malignant melanoma. Excessive TGFb1 activity is an integral part of the fibrotic processes occur-ring in the response to injury. An increased TGFb1 expression has been observed in patients with pulmonary, kidney, and liver fibrosis. In chronic hepatitis, the prolonged stimulation of hepatic stellate

9、 cells being the result of chronic damage to hepatocytes results in the release of profibrogenic abundant factors such as TGFb1 and leads to the development of liver cirrhosis. The results of experimental procedures and treatment known as anti-TGFb1 strategy acting against the fibrosis in various ti

10、ssues leads to hope regarding the use of anti-TGFb1 strategy in clinical practice. (Endokrynol Pol 2013; 64 (5: 384396Key words: TGF b1, TGF beta 1, TGFb1, transforming growth factor beta 1, endocrine gland, liver, cancer, neoplasm, fibrosis, angiogenesis, physiology, pathophysiology, pathologyStres

11、zczenieW artykule pogldowym szczegóowo opisano konsekwencje rozpowszechnienia TGF b1 w organizmie oraz jego wpyw na szereg procesów fizjologicznych i patofizjologicznych. Istotne odrbnoci narzdowe i tkankowe utrudniaj jednoznaczn charakterystyk tej cytokiny. Istniej jednak stae funkcje TGF

12、b1 nie wzbudzajce kontrowersji: uczestniczy w rozwoju podu, regulacji wzrostu i rónicowa-nia komórek, indukuje proces wóknienia i bliznowacenia (proces gojenia rany”, powoduje hamowanie odpowiedzi immunologicznej, uczestniczy w angiogenezie, w rozwoju nowotworów, w procesach zapa

13、lnych - jest wic cytokin wieloczynnociow. Mona wyróni trzy fundamentalne kierunki jego dziaania: I TGFb1 reguluje proliferacj, wzrost, rónicowanie i przemieszczanie komórek; II TGFb1 wykazuje dziaanie immunomodulujce; III TGFb1 wykazuje dziaanie profibrogenne. Dziaanie TGFb1 moe mie c

14、harakter miejscowy i systemowy. Opisano udzia TGFb1 w stanach patologicznych: wrzodziejce zapalenie jelita grubego, choroba Crohna, celiakia, cukrzyca (nefropatia, retinopatia, stopa cukrzycowa, nadcinienie pucne, choroba Alzheimera. TGFb1 i jego receptory s równie przedmiotem zainteresowania e

15、ndokrynologów. Brak zalenej od TGFb1 kontroli wzrostu moe skutkowa onkogenez: rak brodawkowaty, pche-rzykowy i anaplastyczny tarczycy, prostaty, sutka, szyjki macicy, przeyku, odka, jelita grubego, wtroby, NSCLC, czerniak zoliwy. Nadmierna aktywno TGFb1 jest integraln czci procesów wó

16、knienia zachodzcych w odpowiedzi na uszkodzenie. Zwikszon ekspresj TGFb1 stwierdzono m.in. u chorych ze zwóknieniem puc, nerek i wtroby. U chorych z przewlekym zapaleniem wtroby dugotrwaa stymulacja komórek gwiadzistych bdca wynikiem przewlekego stanu uszkadzania hepatocytów skutkuje

17、obfitym uwal-nianiem profibrogennych czynników, w tym TGFb1 prowadzc do rozwoju marskoci wtroby. Wyniki eksperymentalnego postpowania i leczenia, okrelanego jako strategia anty-TGFb1, przeciwdziaajcemu procesowi wóknienia w rónych tkankach stwarzaj nadziej na jego zastosowanie w prakt

18、yce klinicznej. (Endokrynol Pol 2013; 64 (5: 384396Sowa kluczowe: TGF b1, TGF beta 1, TGFb1, transformujcy czynnik wzrostu beta 1, gruczo endokrynny, wtroba, rak, nowotwór, wóknienie, angiogeneza, fizjologia, patofizjologia, patologiaThis work has used information and materials gathered du

19、ring the implementation of the grants funded by the State Committee for Scientific Research (KBN; Poland: 3P05B05322, 3P05B03123 and published in the habilitation dissertation by D.Kajdaniuk: ISBN 978-83-7509-108-3, ISSN 1689-6262.385Endokrynologia Polska 2013; 64 (5P R A C E P O G L D O W ETGF b1 a

20、nd its receptorsThe name transforming growth factor (TGF was introduced by Moses et al. 1, who found so called transformation fibroblast stimulating factor to the can-cer cell phenotype. Later it turned out that there are factors TGF a and b, and the latter also has isoforms. TGF bs previously used

21、names were a reflection of the first descriptions of its actions. It was called factor inhibiting differentiation, stimulating cartilage growth, and sarcoma growth factor. Now it is known that TGFb1 activity is much wider (as described below. In turn, TGF b2 and TGFb3 regulate cell proliferation, gr

22、owth, differentiation and migration. They participate in adipogenesis, chondrogenesis, embryogenesis, tissue remodelling, wound healing, and tumour formation. T ransforming growth factor b, and 40 other proteins, including inhibin A and B, and activin A, AB, B, C, E, BMP2-15 (bone morphogenetic prot

23、eins are included in the family of modulators of cell proliferation, dif-ferentiation and apoptosis, extracellular matrix (ECM synthesis. These proteins play an important role in prenatal development, postnatal growth, reconstruc-tion and maintenance of normal organs structure. TGFb was isolated in

24、1978 24.TGF b is a polypeptide constructed from 112 amino acids, encoded by a gene located on the long arm of chromosome 19. TGF b exists in five isomeric forms marked with symbols from b1 to b5, homologous in 6080%. TGF b1-3 are present in humans, mammals and birds. TGFb4-5 occur in birds and amphi

25、bians. In humans, the predominant isoform is TGFb1, which is synthesised by almost all cells. Other isoforms are expressed in a limited spectrum of cells and tissues. TGF b2 is synthesised in large amounts in glioma cells and keratinocytes. TGFb3 is observed mainly in embryonic heart and lung tissue

26、, and to a negligible extent in the liver, spleen and kidneys 57. TGF b1 is synthesised primarily by platelets, macrophages/ /monocytes, lymphocytes, fibroblasts, epithelial cells 8 and dendritic cells 3. In vitro, TGFb isoforms have a similar biological effect on the tissues, but in vivo the effect

27、 is varied 9. In vivo, these isoforms show differ-ences in the biological effects mainly conditioned by their different tissue distribution, the degree of target cells differentiation and TGFb concentration 3. In the liver, both healthy and with fibrosis, TGFb1 is the most common isoform 10.TGF b1 i

28、s a homodimer with a mass 25 kDa. The sequence of amino acids in TGFb1 proteins from differ-ent species are very stable, which leads to the conclu-sion that in the process of evolution, TGFb has been only slightly altered, and that both in humans and in animals, its function is similar. This hypothe

29、sis is con-firmed by the properties of TGFb demonstrated in in vitro studies on human and animal cells 3, 5. TGFb1 is released from cells as an inactive precursor containing TGF b1 and propeptide LAP (Latency-Associated Pro-tein that are connected by non-covalent linkage 11. In this embodiment, TGFb

30、1 can be stored in the granules of platelets or on the cell surface. TGFb1 is connected (through the LAP by a disulphide bond with LTBP (Latent TGFb Binding Protein. LTBP1-4 is a component of the ECM, and is necessary both for the synthesis of TGF b1 and its storage 7. Changing the conformation of L

31、TBP by the ECM glycoprotein thrombospondin-1 leads to the release from the complex of an active form of TGFb 11. In the blood, TGFb1 occurs in an inac-tive form with a half life of 90 minutes. The half-life of the active form reaches only a few minutes. Thus, the LAP and LTBP mask the epitopes of TG

32、Fb1, and the active form is almost undetectable in the blood and tis-sues (regardless of the method. In the initial phase of TGF b1 activation, a tissue transglutaminase is involved. TGF b1 release from the inactive complex occurs dur-ing its proteolysis under the influence of plasmin and thrombin 7

33、. It is believed that certain factors regulate TGF b1 activity by increasing its synthesis, and others by increasing its bioavailability. TGFb1 synthesis is stimu-lated by physical, mechanical, and biochemical factors 12. Increased TGFb1 activity has been observed in response to angiotensin II 1316,

34、 LDL, glucose, throm-boxane A2. Natural inhibitors of TGFb1 are follistatin, decorin, and a2-macroglobulin 12. In the organism, a series of interactions between the ligands TGFb and their natural inhibitors occur.TGF b signalling activity in the cells is possible only when they have specific membran

35、e receptors which occur as dimeric proteins 6. So far, nine different types of molecules (receptors and proteins having the ability to bind TGFb have been identified. The best known receptors are types I, II, and III 11. The operation of all TGFb isoforms is done by these three types of recep-tors f

36、or TGFb TGFbRI, TGFbRII, and TGFbRIII 17. TGF bRI is a dimer of molecular weight 53 kDa, dimer TGF bRII weight 75 kDa, and TGF bRIII has a mass 280 kDa 17, 18. TGFbRI and TGFbRII are the family of transmembrane receptors, their intracellular fragments have domains with serine-threonine kinase activi

37、ty 19. The extracellular part of TGFbRII by binding the ligand (TGFb activates the intracellular domain of the recep-tor. The created complex joins TGFbRI that determines specificity of TGFb recognition 20. This heteromeric complex is formed by two molecules (dimers TGFbRI, TGF bRII and TGF b 18, 21

38、24. Activated TGFbRII kinase phosphorylates serine fragments of sequence TTSGSGSG in GS domain (domain rich in glycine and serine of TGFbRI, thus leading to activation of serine-386T ransforming growth factor b1 (TGFb1 in physiology and pathology Dariusz Kajdaniuk et al.P R A C E P O G L D O W Ethre

39、onine kinase in the receptor, and thereby starts the signal transduction cascade inside the cell 2, 11, 18, 2127. TGFbRII can indeed bind TGFb independently of the presence the TGFbRI, but without TGFbRI is un-able to transduce a biological signal 28. On the other hand, in the absence of TGFbRII, th

40、e cells are insensi-tive to the action of TGFb 29. TGFbRII is activated in the process of autophosphorylation, while activation of TGFbRI requires a connection to complex of TGFb1-TGF bRII, -TGFbRIII 19. TGFb1 and TGFb3 have a high ability to bind with TGFbRII. TGFb2 exerts its effect only after a p

41、revious presentation by TGFbRIII to the other receptors I and II 30, 31. TGFbRIII is called a betagly-can, which is anchored in the membrane proteoglycan having no enzymatic activity 19, without exerting any intracellular activity. Its role is to present TGFb to the other two receptors. TGFbRIII is

42、the most abundant receptor subtype in most cells 32, 33. TGFbRIII is located on the cell surface binding the ligand 34 it has a high affinity for all three isoforms of TGFb. In its absence, the cells do not respond to TGFb2, whereas the response of cells to the other two isoforms of the cytokine is

43、maintained 27. The action of TGFb in he-patic stellate cells (HSC can be modulated by TGFbRIII 34. In these cells, it is additionally important because the expression of TGFb2 here is low 35. TGFbRIII may also be an inhibitor of the signal transduction by pre-vention of TGFb connections to TGFbRII a

44、nd TGFbRI in the mechanism independent from ligand binding. In such a situation, it fulfills the function of regulating the ligand binding with the remaining two receptors 36. TGFbRIIIs soluble form, by binding the ligand, neutralises it 34. The final effect of TGFb1 depends on its bioavailability,

45、the distribution of receptors in tissues, and the target cell type 12, 37.After binding TGFb with receptors, signal trans-duction occurs to the nucleus with the participation of proteins Smad present in the cytoplasm, which ultimately results in the influencing of the processes of transcription and

46、translation of TGFb-dependent genes i.e. showing typical for TGFb activity 18. System of intracellular transmitters Smad proteins is thus a specific link between receptors and the cellular nucleus 2, 3840. After activating serine-threonine ki-nase in TGFbRI, it comes to further signal transduction b

47、y phosphorylation of cytoplasmic proteins Smad2 23 and Smad3 23, 41 binding to receptors. Similar in the structure Smad2 and Smad3 are classified as a group called R-Smad (receptor regulated Smads. Phosphorylated R-Smad can be separated from the connection to the receptor and from protein SARA 23. A

48、uxiliary protein SARA (Smad Anchor for Receptor Activation is a cytoplasmic protein anchored in the cell membrane that binds both the R-Smad and TGFb/TGFbRII/TGFbRI. SARA participates in the early stag-es of signal transduction recognising the non phos-phorylated R-Smad joins it to the the newly for

49、med receptor complex, and is dissociated itself 42. Phos-phorylated R-Smad forms a complex with the co-Smad (common partner Smad namely Smad4, and so the newly formed complex is transported to the nucleus 26, 42, where it regulates the transcription of TGFb-dependent genes 43. Thus, phosphorylated S

50、mad act as transcription factors, which by binding to specific DNA sequences are responsible for the transcription of specific genes 2, 11, 19, 41. Smad4 co-operates with other transcription factors in the regulation of TGF b-dependent gene expression therefore it is a grasping point for these facto

51、rs. Signal transduction from the receptor to the nucleus can be inhibited by a protein Smad6 and Smad7 called I-Smads (Smads inhibitors, which despite the absence of motif in its structure which can be phosphorylated by receptor kinases, are able to interact with membrane receptors, thus impairing t

52、heir interaction with the R-Smad 26. Smad7 expression is induced by TGFb, leading to in-hibition of the cellular response to this cytokine. It is therefore an autoregulation in the negative feedback mechanism 26, 42. Smad7 forms a stable complex with activated TGFbRI and thus impairs the phos-phoryl

53、ation of Smad and inhibits signalling cascade 38, 43, 44. There are known also proteins Smad 1, 5, 8, which transmit impulses from other ligands related to TGFb, including BMPs 23. Overall in the Smad sys-tem, ten different proteins carrying a signal have been identified which were activated by the

54、TGFb-receptor complex RI-III 2. Under disease conditions, Smads also interact with other signalling pathways, such as the mitogen-activated protein kinase and nuclear factor -B pathways 45.TGF b1 in physiology and pathophysiologyThe consequence of TGFb1prevalence in the organism is its significant i

55、nfluence on a number of physiological and pathophysiological processes. As a result of this, interrelations with other cytokines and biologically active substances as well as organ and tis-sue distinctiveness hinder unambiguous characterisa-tion of TGFb1. However, there are constant functions of the

56、 cytokine inducing no controversy: it participates in foetal development, control of cell growth and dif-ferentiation, induces fibrosis and scar formation (the process of wound healing, causes the suppression of immune response, is involved in angiogenesis, the development of tumours, and inflammato

57、ry processes 6, 11, 42, 4648. Thus, TGF b1 is a multifunctional cytokine.387Endokrynologia Polska 2013; 64 (5P R A C E P O G L D O W EThere are three fundamental directions of its activities:I. TGFb1 regulates cell proliferation, growth, differentiation and cells movement. Growth factors/ /cytokines

58、 may affect stimulating or inhibiting on the cell proliferation and differentiation by linking to specific receptors, which triggers a cascade of signals leading to the activation or repression of various genes. Growth factors acting on cells in the resting state or in the G0 phase introduce them in

59、to the cell cycle. Growth factors called competence factors bring the cells into the G1 phase and conduct them through this phase, while under the influence of growth factors termed progressive factors DNA synthesis occurs. Passing through the G1 phase requires stimulation by growth factors throughout its duration (a few hours. If this stimulating signal is broken, the cell retu