Skip to main content
Intended for healthcare professionals
Free access
Research article
First published November 2006

Interleukin-6-induced Activation of Signal Transducer and Activator of Transcription-3 in Ruptured Rotator Cuff Tendon

Abstract

The aim of this study was to examine interleukin-6 production and the activation of signal transducer and activator of transcription-3 (STAT3) in ruptured rotator cuff tendon. Specimens of ruptured rotator cuff tendons were analysed using real-time reverse transcriptase polymerase chain reaction, Western blotting and immunohistochemistry. Specimens of co-existing inflammatory subacromial synovia were examined for comparison. The level of interleukin-6 messenger RNA was increased in ruptured rotator cuff tendon as well as in subacromial synovium. Western blot analysis showed constitutive production of activated, phosphorylated STAT3 in ruptured rotator cuff tendon and co-existing subacromial synovium. Immunohistochemical examination detected cells producing interleukin-6, interleukin-6 receptor and phosphorylated STAT3 in ruptured rotator cuff tendon, mainly in proliferative vessels and, to a lesser extent, in tendon fibroblasts around the vessels. This study demonstrates that activation of STAT3 induced by interleukin-6 is promoted mainly by proliferative vessels in ruptured rotator cuff tendon.

References

1. Gotoh M, Hamada K, Yamakawa H, Yanagisawa K, Nakamura M, Yamazaki H, et al: Interleukin-1-induced subacromial synovitis and shoulder pain in rotator cuff diseases. Rheumatology (Oxford) 2001; 40: 995–1001.
2. Neer CS 2nd: Anterior acromioplasty for the chronic impingement syndrome of the shoulder: A preliminary report. J Bone Joint Surg Am 1972; 54: 41–50.
3. Soifer TB, Levy HJ, Soifer FM, Kleinbart F, Vigorita V, Bryk E: Neurohistology of the subacromial space. Arthroscopy 1996; 12: 182–186.
4. Tomita Y, Ozaki J, Sakurai G, Kando T, Nakagaki K, Tamai S: Neurohistology of the subacromial bursa in rotator cuff tear. J Orthop Sci 1997; 2: 295–300.
5. Vangsness CT Jr, Ennis M, Taylor JG, Atkinson R: Neural anatomy of the glenohumeral ligaments, labrum, and subacromial bursa. Arthroscopy 1995; 11: 180–184.
6. Mehta S, Gimbel JA, Soslowsky LJ: Etiologic and pathogenetic factors for rotator cuff tendinopathy. Clin Sports Med 2003; 22: 791–812.
7. Hashimoto T, Nobuhara K, Hamada T: Pathologic evidence of degeneration as a primary cause of rotator cuff tear. Clin Orthop Relat Res 2003; 415: 111–120.
8. Kannus P, Jozsa L: Histopathological changes preceding spontaneous rupture of a tendon. A controlled study of 891 patients. J Bone Joint Surg Am 1991; 73: 1507–1525.
9. Sharma P, Maffulli N: Tendon injury and tendinopathy: Healing and repair. J Bone Joint Surg Am 2005; 87: 187–202.
10. Khan KM, Cook JL, Bonar F, Harcourt P, Astrom M: Histopathology of common tendinopathies. Update and implications for clinical management. Sports Med 1999; 27: 393–408.
11. Ireland D, Harrall RL, Curry V, Holloway G, Hackney R, Hazleman BL, et al: Multiple changes in gene expression in chronic human Achilles tendinopathy. Matrix Biol 2001; 20: 159–169.
12. Khan KM, Cook JL, Kannus P, Maffulli N, Bonar SF: Time to abandon the ‘tendonitis’ myth. BMJ 2002; 324: 626–627.
13. Riley G: The pathogenesis of tendinopathy. A molecular perspective. Rheumatology (Oxford) 2004; 43: 131–142.
14. Hodge DR, Hurt EM, Farrar WL: The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 2005; 41: 2502–2512.
15. Langberg H, Olesen JL, Gemmer C, Kjaer M: Substantial elevation of interleukin-6 concentration in peritendinous tissue, in contrast to muscle, following prolonged exercise in humans. J Physiol 2002; 542: 985–990.
16. Langberg H, Skovgaard D, Karamouzis M, Bulow J, Kjaer M: Metabolism and inflammatory mediators in the peritendinous space measured by microdialysis during intermittent isometric exercise in humans. J Physiol 1999; 515: 919–927.
17. Langberg H, Skovgaard D, Petersen LJ, Bulow J, Kjaer M: Type I collagen synthesis and degradation in peritendinous tissue after exercise determined by microdialysis in humans. J Physiol 1999; 15: 299–306.
18. Skutek M, van Griensven M, Zeichen J, Brauer N, Bosch U: Cyclic mechanical stretching enhances secretion of interleukin 6 in human tendon fibroblasts. Knee Surg Sports Traumatol Arthrosc 2001; 9: 322–326.
19. Nakama LH, King KB, Abrahamsson S, Rempel DM: Evidence of tendon microtears due to cyclical loading in an in vivo tendinopathy model. J Orthop Res 2005; 23: 1199–1205.
20. Hodge DR, Hurt EM, Farrar WL: The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 2005; 41: 2502–2512.
21. Darnell JE Jr: STATs and gene regulation. Science 1997; 277: 1630–1635.
22. Lee C, Lim HK, Sakong J, Lee YS, Kim JR, Baek SH: Janus kinase-signal transducer and activator of transcription mediates phosphatidic acid-induced interleukin (IL)-1 beta and IL-6 production. Mol Pharmacol 2006; 69: 1041–1047.
23. Blaine TA, Kim YS, Voloshin I, Chen D, Murakami K, Chang SS, et al: The molecular pathophysiology of subacromial bursitis in rotator cuff disease. J Shoulder Elbow Surg 2005; 14: 84S–89S.
24. Voloshin I, Gelinas J, Maloney MD, O'Keefe RJ, Bigliani LU, Blaine TA: Proinflammatory cytokines and metalloproteases are expressed in the subacromial bursa in patients with rotator cuff disease. Arthroscopy 2005; 21:1076.
25. Ben-Shahar Y, Robichon A, Sokolowski MB, Robinson GE: Influence of gene action across different time scales on behavior. Science 2002; 296: 741–744.
26. Yuan J, Murrell GA, Wei AQ, Wang MX: Apoptosis in rotator cuff tendinopathy. J Ortho Res 2002; 20: 1372–1379.
27. Fenwick SA, Hazleman BL, Riley GP: The vasculature and its role in the damaged and healing tendon. Arthritis Res 2002; 4: 252–260.
28. Wei LH, Kuo ML, Chen CA, Chou CH, Lai KB, Lee CN, et al: Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene 2003; 22: 1517–1527.
29. Hilfiker-Kleiner D, Limbourg A, Drexler H: STAT3-mediated activation of myocardial capillary growth. Trends Cardiovasc Med 2005; 15: 152–157.
30. Hilfiker-Kleiner D, Hilfiker A, Fuchs M, Kaminski K, Schaefer A, Schieffer B, et al: Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ Res 2004; 95: 187–195.
31. Newman JS, Adler RS, Bude RO, Rubin JM: Detection of soft-tissue hyperemia: Value of power Doppler sonography. Am J Roentgenol 1994; 163: 385–389.
32. Mohana-Borges AV, Chung CB, Resnick D: MR imaging and MR arthrography of the postoperative shoulder: Spectrum of normal and abnormal findings. Radiographics 2004; 24: 69–85.
33. Freeland AE, Tucci MA, Barbieri RA, Angel MF, Nick TG: Biochemical evaluation of serum and flexor tenosynovium in carpal tunnel syndrome. Microsurgery 2002; 22: 378–385.
34. Noma H, Funatsu H, Yamasaki M, Tsukamoto H, Mimura T, Sone T, et al: Pathogenesis of macular edema with branch retinal vein occlusion and intraocular levels of vascular endothelial growth factor and interleukin-6. Am J Ophthalmol 2005; 140: 256–261.
35. Bjur D, Alfredson H, Forsgren S: The innervation pattern of the human Achilles tendon: Studies of the normal and tendinosis tendon with markers for general and sensory innervation. Cell Tissue Res 2005; 320: 201–206.
36. Azzolina A, Bongiovanni A, Lampiasi N: Substance P induces TNF-α and IL-6 production through NFκB in peritoneal mast cells. Biochim Biophys Acta 2003; 1643: 75–83.
37. Ohberg L, Alfredson H: Ultrasound guided sclerosis of neovessels in painful chronic Achilles tendinosis: Pilot study of a new treatment. Br J Sports Med 2002; 36: 173–175.
38. Shouda T, Yoshida T, Hanada T, Wakioka T, Oishi M, Miyoshi K, et al: Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J Clin Invest 2001; 108: 1781–1788.
39. Suzuki A, Hanada T, Mitsuyama K, Yoshida T, Kamizono S, Hoshino T, et al: CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. J Exp Med 2001; 193: 471–481.

Cite article

Cite article

Cite article

OR

Download to reference manager

If you have citation software installed, you can download article citation data to the citation manager of your choice

Share options

Share

Share this article

Share with email
EMAIL ARTICLE LINK
Share on social media

Share access to this article

Sharing links are not relevant where the article is open access and not available if you do not have a subscription.

For more information view the Sage Journals article sharing page.

Information, rights and permissions

Information

Published In

Article first published: November 2006
Issue published: November 2006

Keywords

  1. Ruptured rotator cuff tendon
  2. Interleukin-6
  3. Signal transducer and activator of transcription-3 (STAT3)

Rights and permissions

© 2006 SAGE Publications.
Request permissions for this article.
PubMed: 17294994

Authors

Affiliations

K Nakama
Department of Orthopaedic Surgery, Kurume University, Fukuoka, Japan
M Gotoh
Department of Orthopaedic Surgery, Kurume University Medical Centre, Fukuoka, Japan
T Yamada
Department of Orthopaedic Surgery, Kurume University, Fukuoka, Japan
Y Mitsui
Department of Orthopaedic Surgery, Kurume University, Fukuoka, Japan
H Yasukawa
Cardiovascular Research Institute and Internal Medicine III, Kurume University, Fukuoka, Japan
T Imaizumi
Cardiovascular Research Institute and Internal Medicine III, Kurume University, Fukuoka, Japan
F Higuchi
Department of Orthopaedic Surgery, Kurume University Medical Centre, Fukuoka, Japan
K Nagata
Department of Orthopaedic Surgery, Kurume University, Fukuoka, Japan

Notes

Address for correspondence Dr M Gotoh Department of Orthopaedic Surgery, Kurume University Medical Centre, 155 Kokubu-machi, Kurume, Fukuoka 839-0863, Japan. E-mail: [email protected]

Metrics and citations

Metrics

Journals metrics

This article was published in Journal of International Medical Research.

VIEW ALL JOURNAL METRICS

Article usage*

Total views and downloads: 220

*Article usage tracking started in December 2016


Altmetric

See the impact this article is making through the number of times it’s been read, and the Altmetric Score.
Learn more about the Altmetric Scores



Articles citing this one

Receive email alerts when this article is cited

Web of Science: 28 view articles Opens in new tab

Crossref: 25

  1. Biology and physiology of tendon healing
    Go to citation Crossref Google Scholar
  2. Inhibiting JAK1, not NF-κB, reverses the effect of pro-inflammatory cy...
    Go to citation Crossref Google Scholar
  3. In vitro effect of triamcinolone and platelet-rich plasma on cytokine ...
    Go to citation Crossref Google Scholar
  4. Regulating Macrophages through Immunomodulatory Biomaterials Is a Prom...
    Go to citation Crossref Google Scholar
  5. The inhibitory effect of tocilizumab on systemic bone loss and tendon ...
    Go to citation Crossref Google Scholar
  6. Cytokines, Chemokines, Alpha-2-Macroglobulin, Growth Factors
    Go to citation Crossref Google Scholar
  7. Reparative and Maladaptive Inflammation in Tendon Healing
    Go to citation Crossref Google Scholar
  8. Effects of Long-Term Methotrexate, Infliximab, and Tocilizumab Adminis...
    Go to citation Crossref Google Scholar
  9. A2A adenosine receptors are involved in the reparative response of ten...
    Go to citation Crossref Google Scholar
  10. Upregulation of HSP72 attenuates tendon adhesion by regulating fibrobl...
    Go to citation Crossref Google Scholar
  11. The roles of inflammatory mediators and immunocytes in tendinopathy
    Go to citation Crossref Google Scholar
  12. Synovial fluid biomarkers: association with chronic rotator cuff tear ...
    Go to citation Crossref Google Scholar
  13. Targeting Inflammation in Rotator Cuff Tendon Degeneration and Repair
    Go to citation Crossref Google Scholar
  14. The influence of chronic IL-6 exposure, in vivo , on rat Achilles tend...
    Go to citation Crossref Google Scholar
  15. Shoulder pain and intra-articular interleukin-8 levels in patients wit...
    Go to citation Crossref Google Scholar
  16. The low level laser therapy (LLLT) operating in 660 nm reduce gene exp...
    Go to citation Crossref Google Scholar
  17. Role of Serum Fibrinogen Levels in Patients with Rotator Cuff Tears
    Go to citation Crossref Google Scholar
  18. Increased expression of IL-6 family members in tendon pathology
    Go to citation Crossref Google Scholar
  19. Biological Solutions in Rotator Cuff Healing
    Go to citation Crossref Google Scholar
  20. Regulation of gene expression in human tendinopathy
    Go to citation Crossref Google Scholar
  21. Repeated muscle biopsies through a single skin incision do not elicit ...
    Go to citation Crossref Google Scholar
  22. The role of pro‐inflammatory and immunoregulatory cytokines in tendon ...
    Go to citation Crossref Google Scholar
  23. Lifestyle and metabolic factors in relation to shoulder pain and rotat...
    Go to citation Crossref Google Scholar
  24. Effect of pro-inflammatory and immunoregulatory cytokines on human ten...
    Go to citation Crossref Google Scholar
  25. Cytokines and apoptosis in supraspinatus tendinopathy
    Go to citation Crossref Google Scholar

Figures and tables

Figures & Media

Tables

View Options

View options

PDF/ePub

View PDF/ePub

Get access

Access options

If you have access to journal content via a personal subscription, university, library, employer or society, select from the options below:


Alternatively, view purchase options below:

Purchase 24 hour online access to view and download content.

Access journal content via a DeepDyve subscription or find out more about this option.