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Rheumatology 2001; 40: 995-1001
© 2001 British Society for Rheumatology

Original Papers

Interleukin-1-induced subacromial synovitis and shoulder pain in rotator cuff diseases

M. Gotoh1,2,3,, K. Hamada1, H. Yamakawa1, K. Yanagisawa1, M. Nakamura2, H. Yamazaki2, Y. Ueyama2, N. Tamaoki2, A. Inoue3 and H. Fukuda1

1 Department of Orthopaedic Surgery,
2 Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193 and
3 Department of Orthopaedic Surgery, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. To determine the relationship between the expression of interleukin-1ß (IL-1ß) and IL-1 receptor antagonists (IL-1ra) in the subacromial bursa and shoulder pain in rotator cuff diseases.

Methods. Synovial specimens were analysed using various methods including reverse transcriptase–polymerase chain reaction (RT–PCR), immunohistochemistry and in situ RT–PCR. Thirty-nine patients with rotator cuff diseases were candidates. The degree of their shoulder pain was evaluated using a visual analogue scale.

Results. The mRNA expression levels of the cytokines were significantly correlated with the degree of pain [IL-1ß: r=0.782; secreted IL-1ra (sIL-1ra): r=0.756; intracellular IL-1ra (icIL-1ra): r=0.806, P<0.001, respectively]. The combined results of immunohistochemistry and in situ RT–PCR analysis indicated that both synovial lining and sublining cells produce IL-1ß, while synovial lining cells predominantly produce icIL-1ra and sublining cells secrete sIL-1ra.

Conclusions. The differential regulation of the two forms of IL-1ra mRNAs may play an important role in shoulder pain in rotator cuff diseases, regulating IL-1-induced subacromial synovitis.

KEY WORDS: Interleukin-1ß, Interleukin-1 receptor antagonist, Shoulder pain, Subacromial bursa, Rotator cuff diseases.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
The shoulder joint is composed of two synovial cavities, the subacromial bursa (SAB) and the glenohumeral joint. The rotator cuff is interposed between these two cavities and works as a motor source and stabilizer of the shoulder joint. Rotator cuff diseases occur frequently in middle-aged and elderly patients, and pose a significant problem as they are associated with severe shoulder pain. However, few studies have dealt with the mechanisms responsible for shoulder pain in rotator cuff diseases.

It is generally accepted that the SAB is the main source of pain in rotator cuff diseases [1–3], and the following two reasons have been proposed: the SAB is anatomically vulnerable to friction against the undersurface of the acromion and the coracoacromial ligament, so that secondary subacromial bursitis may readily occur; the SAB has also been assessed for innervation, including markers for primary afferent nociceptors.

Histologically, the synovial tissue of the SAB tends to undergo proliferative or degenerative changes in rotator cuff diseases, but the bursal inflammation does not include prominent polymorphonuclear cell infiltration [4, 5]. This prompted us to examine the relationship between inflammatory cytokines which stimulate the peripheral nociceptors and shoulder pain in rotator cuff diseases.

Interleukin-1 (IL-1) is considered to be an important reactive factor during infection and inflammation [6, 7]. Because IL-1ß is released during inflammation, it may play a role in hyperalgesia by indirectly activating polymodal receptors [8–10]. IL-1 receptor antagonist (IL-1ra) competitively inhibits binding of IL-1{alpha} and IL-1ß to type I and II IL-1 receptors [11]. Induction of IL-1ra may repress partially the homeostatic mechanism regulating the inflammatory response, and the ratio of IL-1ß to IL-1ra is probably a critical factor in determining the severity of the inflammatory response [12]. A low ratio is correlated with rapid resolution of disease, whereas a high ratio tends to prolong recovery periods [13].

In rotator cuff diseases, subacromial synovitis is responsible for the generation of shoulder pain, and its severity may correlate with the intensity of pain [14]. In the present study, we semi-quantitatively examined mRNA expression levels of IL-1ß and two forms of IL-1ra [secreted IL-1ra (sIL-1ra) and intracellular IL-1ra (icIL-1ra) mRNA] using reverse transcriptase–polymerase chain reaction (RT–PCR) in rotator cuff diseases. We also employed immunohistochemistry and in situ RT–PCR to detect the cells producing these cytokines.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Tissue samples
Synovial tissue specimens of the SAB were obtained from 39 patients with rotator cuff diseases (10 subacromial bursitis, nine partial-thickness tears and 20 full-thickness tears) during surgery. The average age was 56 yr (range 39–76 yr). Patients with contracted shoulder (less than 100° passive elevation) were excluded from this study. The SAB specimens were harvested from the surrounding tissue of the greater tuberosity. The average duration of pain in the patients was 1 yr (4 months to 8 yr). Synovial tissue specimens were stored at -80°C for total cellular RNA isolation. Specimens were also fixed in 4% paraformaldehyde in phosphate buffer for 2 h at room temperature and embedded in paraffin. Control SAB specimens were obtained during surgery from 10 patients with anterior shoulder instability. These control groups had no resting pain at any time and showed no symptoms of subacromial impingement. All specimens were obtained with informed consent.

Shoulder pain evaluation using the visual analogue scale (VAS)
The degree of shoulder pain was evaluated in each patient before the operation using the VAS as previously described [14–16]. The degree of pain was graded from 0 to 10 according to a subjective symptom scale: 0, no pain; 5, moderate; 10, severe pain. Patients' symptoms were recorded by hospital staff blind to this study.

Analysis by RT–PCR
First-strand cDNA synthesis was carried out at 23°C for 10 min, 42°C for 60 min in 20 µ1 of 50 mM Tris–Cl, 75 mM KCl, 3 mM MgCl2, 0.1 M dethiothreitol (DTT), 1 mM deoxynucleotide triphosphate mixture, 65 U of human placental ribonuclease inhibitor (TaKaRa, Osaka, Japan), 100 pmol oligonucleotide random primer (TaKaRa) and 20 U of reverse transcriptase (GIBCO BRL, Gaithersburg, MD, USA). After denaturation, cytokine-specific cDNA fragments were amplified with 2.5 U Taq DNA polymerase by the hot-start procedure (TOYOBO, Shiga, Japan; denaturation at 94°C for 1 min, annealing at 55°C for 30 s, and extension at 72°C for 1 min, 25 cycles) with primers specific for IL-1ß (sense: 5-AAACAGATGAAGTGCTCCTTCAGG-3, anti- sense: 5-TGGAGAACACCACTTGTTGCTCCA-3), sIL-1ra (sense: 5-GAAGGTCTTCTGGTTAACATCCCAG-3, anti-sense: GAATGGAAATCTGCAGAGGCCTCCGC-3) and icIL-1ra (sense: 5-GTACTACTCGT-CCTCCTGG-3, anti-sense: 5-CAGAAGACCTCCTG-TCCTATGAGG-3).

PCR amplification of specific cDNA fragments of the cytokines was proportional to the amount of starting material under these conditions [17, 18]. Total cellular RNA prepared from the CHU-2 cell line was used as a positive control for IL-1ß. RNA preparations from normal lung tissues were used as a positive control for sIL-1ra, and preparations from skin specimens were used for icIL-1ra. Human tissues were obtained with the approval of the Tokai University School of Medicine Institutional Review Board.

PCR products separated from 3% agarose gels were blotted on to membranes. The blots were hybridized with 32P-labelled oligonucleotide probes (IL-1ß: 5-GACACATGGGATAACGAGGCTTATGTGCAC-3, both IL-1ra: 5-GGCTTGCATCTTGCTGGATTTTCTCCC-3) at 55°C for 16 h. The blots were exposed to Kodak RP film at -80°C with double intensifying screens. Signal intensity was quantified with the Interactive Build Analysis System (Carl Zeiss, Germany). The amounts of PCR product in each sample relative to the positive controls were calculated. ß-actin (sense: 5-CCTTCCTGGGCATGGAGTCCTG, anti-sense: 5-GGAGCAATGATCTTGATCTTC-3, internal probe: 5-CGCAAAGACCTGTACCGCCAACACAGTGCTG-3) was used as a control to ensure equivalent loading of RNA in each lane.

Immunohistochemistry
Paraffin-embedded sections were subjected to immunohistochemical analysis with rabbit anti-human IL-1ß and IL-1ra polyclonal antibodies (kindly provided by Ohtsuka Pharmaceutical Co. Ltd, Tokushima, Japan) [19]. After blocking of endogenous peroxidase activity (methylalcohol, 0.1% hydrogen), protease digestion [0.1% trypsin (Sigma Chemical Co., St Louis, MO USA) at 37°C for 20 min] and blocking of non-specific binding with goat serum (1:10), the specimens were incubated with anti-IL-1ß or anti-IL-1ra antibody (1:100) at 4°C overnight. The sections were then incubated with horseradish peroxidase (HRP)-labelled anti-rabbit IgG (1:50) for 30 min. The reaction products were visualized with 0.2% diaminobenzidine tetrahydrochloride (DAB) in 50 mM Tris–Cl (pH 7.6) with 0.003% H2O2 for 5 min at room temperature.

In situ RT–PCR
Sections of 4 µm thickness on silanized glass slides were used for in situ RT–PCR (Perkin-Elmer, CA, USA). The sections were deparaffinized, hydrated and air dried, and then fixed with 4% paraformaldehyde in phosphate buffer for 8 h at room temperature. The sections were digested in 2 mg/ml pepsin in 0.1 N HCl for 40 min at room temperature, soaked in 100% ethanol for 1 min, and then DNA was digested with 10 U of RNase-free DNase (Boehringer Mannheim, Germany) at 37°C overnight. The cDNAs were reversed transcribed with 500 U of reverse transcriptase (SuperScript II, GIBCO BRL) in 50 mM Tris–Cl (pH 7.6), 75 mM KCl, 3 mM MgCl2, 0.1 M DTT, 1 mM deoxynucleotide triphosphate mixture, 130 U of human placental ribonuclease inhibitor (TaKaRa) and 100 pmol random oligonucleotide primer (TaKaRa) at 42°C for 60 min. The slides were then rinsed sequentially in H2O and 100% ethanol, and air dried. PCR was performed with 20 U of Taq DNA polymerase (TOYOBO) in 50 µm reaction mixtures [12.9 µM digoxigenin (DIG)-dUTP (Boehringer Mannheim, USA); 10 mM Tris–HCl pH 8.3; 1.5 mM MgCl2; 0.25 mM dATP, dCTP, dGTP, dTTP; 50 ng of specific primer pairs]. The reverse transcribed cDNAs were pre-heated to 94°C for 3 min, and cDNA fragments were amplified by 20 cycles of in situ PCR (denaturation at 94°C for 1 min; annealing and extension at 55°C for 1 min). RT and PCR were performed in chambers covered with concave silicon rubber diaphragms and steel cover clips in a slidecycler (Perkin-Elmer). After washing, the PCR products with DIG were incubated with rabbit anti-DIG antibody (Boehringer Mannheim) for 30 min, and incubated for 30 min with HRP-labelled sheep anti-rabbit antibody. Reaction products were visualized with 0.2% DAB in 50 mM Tris–HCl (pH 7.6) with 0.003% H2O2 for 5 min at room temperature. Successful PCR reactions were confirmed by treatment without DNase digestion or RT reaction [20].

Statistical analysis
Spearman's rank correlation test was used for the analysis of possible relationships among the different parameters recorded in this study. The Mann–Whitney U-test was used for comparisons of parameters between controls and patients with rotator cuff diseases.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Shoulder pain evaluation in rotator cuff diseases
Thirty-nine patients with rotator cuff diseases were examined. The degree of shoulder pain was estimated using a pain scale according to the VAS. The score of the VAS in patients with rotator cuff diseases ranged from 3 to 10 (mean value 6.5), compared with that of controls who uniformly showed 0. The degree of pain in patients with rotator cuff diseases was significantly higher than in controls (P<0.0001). When the rotator cuff diseases were divided into two groups, i.e. non-perforating and perforating, 19 patients in the non-perforating group (10 subacromial bursitis and nine partial-thickness tears) showed a greater degree of pain than 20 patients in the perforating group (20 full-thickness tears) (P<0.001). These results were consistent with our previous report [14].

Cytokine mRNA expression levels in rotator cuff diseases
Cytokine mRNAs (IL-1ß, sIL-1ra and icIL-1ra) were detected by RT–PCR in synovial samples of the SAB from patients with rotator cuff diseases. The expression levels of IL-1ß and its receptor antagonist mRNAs (sIL-1ra, icIL-1ra) were significantly higher in patients with rotator cuff diseases than in controls (Fig. 1AGo–C; P<0.001).



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  		FIG. 1. mRNA expression levels of (A) IL-1ß, (B) sIL-1ra and (C) icIL-1ra in the SAB semi-quantified by RT–PCR.

 

Correlation between cytokine mRNA expression levels and shoulder pain in patients with rotator cuff diseases
We next examined the relationships between mRNA expression levels of the cytokines and the degree of pain measured by the VAS in patients with rotator cuff diseases. The mRNA expression levels of IL-1ß and its receptor antagonists (sIL-1ra, icIL-1ra) were significantly correlated with the degree of pain (IL-1ß: r=0.782; sIL-1ra: r=0.756; icIL-1ra: r=0.806; P<0.001;Fig. 2AGo–CGo).



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  		FIG. 2. Correlation between the pain scale and cytokine mRNA expression levels. (A) IL-1ß mRNA expression level in the SAB. (B) sIL-1ra mRNA expression level in the SAB. (C) icIL-1ra mRNA expression level in the SAB.

 

Correlation between the two forms of IL-1ra and IL-1ß mRNA expression level
In the third step, we evaluated the correlation between the level of IL-1ß mRNA expression and the relative ratio (sIL-1ra mRNA to icIL-1ra mRNA) using RT–PCR. The relative ratio significantly decreased in proportion to the increase in IL-1ß mRNA expression (Fig. 3Go, r=0.672, P<0.001, n=28).



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  		FIG. 3. Correlation between the level of IL-1ß mRNA expression and the relative ratio of the two forms of IL-1ra (sIL-1ra mRNA/icIL-1ra mRNA).

 

Cells producing IL-1ß and its receptor antagonists
Immunohistochemical analysis with anti-IL-1ß antibody demonstrated positive staining in both synovial lining and sublining cells, vessels, infiltrating mononuclear cells and synovial fibroblasts (Fig. 4Go). Immunohistochemistry with anti-IL-1ra antibody also showed positive staining identical to the IL-1ß-producing cells (Fig. 4Go).



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  		FIG. 4. Localization of IL-1ß (top) and IL-1ra (bottom) in SAB synovial specimens in rotator cuff diseases (x600). The sections were consecutively stained by haematoxylin and eosin (HE, left) and immunohistochemistry (IHC, right).

 
In the control synovial specimens of the SAB, inflammatory cells around the vessels and the vessels themselves showed positive immunoreactivity of IL-1ß and its receptor antagonists, although the number of positive cells was negligible compared with the synovial specimens from patients with rotator cuff diseases (data not shown).

Thus, in the number of cytokine-producing cells, marked differences were seen between patients with rotator cuff diseases and controls.

Cells producing mRNA of IL-1ß and the two forms of receptor antagonist in rotator cuff diseases
In immunohistochemistry, we found positive immunoreactivity of IL-1ß and IL-1ra protein in the same regions (synovial lining and sublining layer). To detect localization of cells producing IL-1ß and its receptor antagonists (sIL-1ra, icIL-1ra) at the mRNA level, in situ RT–PCR was exclusively employed for the specimens from patients with rotator cuff diseases. A variety of cells (vessels, infiltrating mononuclear cells and synovial fibroblasts) were shown to express cytokine mRNAs in the SAB. The sublining cells expressed sIL-1ra mRNA in particular, while the synovial lining cells preferentially expressed icIL-1ra mRNA (Fig. 5Go).



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  		FIG. 5. Localization of mRNAs encoding these cytokines in SAB synovial specimens in rotator cuff diseases detected by in situ RT–PCR (x600). The sections were consecutively stained by haematoxylin and eosin (HE, left) and in situ RT–PCR (right).

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Conventionally, inflammation of the SAB has been implicated as a source of shoulder pain, and `bursitis’ has been frequently used in diagnosis [5]. Several morphological studies, however, have demonstrated scarcity of infiltration with inflammatory cells in the SAB from patients diagnosed as having subacromial bursitis [4, 5]. During inflammation, so-called hyperalgesia occurs, which is characterized by intensified pain with a reduced threshold to somatic stimulation [21]. Because IL-1ß is released during inflammation, it plays an important role in such hyperalgesia by indirectly activating polymodal receptors [3, 8–10]. This gave rise to the hypothesis that inflammatory cytokines produced in the SAB, i.e. IL-1ß and IL-1ra, are involved in the generation of shoulder pain in rotator cuff diseases even when the infiltration with inflammatory cells is not prominent.

IL-1ra has two different isoforms (sIL-1ra and icIL-1ra), but their roles in the inflammatory cytokine network have not been clarified as yet. In this study, we analysed mRNA expression levels of IL-1ß, sIL-1ra and icIL-1ra semi-quantitatively to examine the correlation between its expression levels and shoulder pain in rotator cuff diseases. The mRNA expression levels of these cytokines were significantly higher in rotator cuff diseases than in controls (P<0.001), consistent with the results of the VAS. In addition, cytokine mRNA expression levels were proportionally correlated with the degree of shoulder pain (VAS). Thus, our data suggest that the mRNA expression levels of IL-1ß, sIL-1ra and icIL-1ra in the SAB reflect the degree of shoulder pain in rotator cuff diseases.

The relative ratio (sIL-1ra:icIL-1ra) significantly decreased with increased levels of IL-1ß mRNA expression level. In human synovial fibroblasts and dermal fibroblasts, IL-1ra mRNA is regulated in a time- and dose-dependent manner by lipopolysaccharide (LPS) and phorbol myristate acetate (PMA) (their relative IL-1ra induction efficacy; PMA>LPS) [22]. In addition, LPS preferentially induces sIL-1ra mRNA, while PMA differentially induces icIL-1ra mRNA, suggesting that the regulation of the two forms of IL-1ra mRNA depends on the inflammatory response. In the present study, the relative production of sIL-1ra mRNA vs icIL-1ra mRNA in the SAB depended on the level of IL-1ß mRNA expression at the site; the production of icIL-1ra mRNA was relatively higher compared with that of sIL-1ra, as the severity of subacromial synovitis worsened.

icIL-1ra acts either extracellularly when released from injured cells, or intracellularly by binding to IL-1 receptors prior to external expression [23]. In contrast, the production of sIL-1ra provides the advantage of allowing this peptide to be available (secreted) and induced without requiring cell damage or death [24]. These findings strongly suggest that icIL-1ra does not contribute to IL-1 antagonism in the extracellular milieu, and indicate the disadvantage of icIL-1ra to sIL-1ra. The present study demonstrated that icIL-1ra mRNA was relatively up-regulated compared with sIL-1ra mRNA, in proportion to the increase in IL-1ß mRNA expression. In view of these findings, it seems that the preferential increase in icIL-1ra mRNA production partly results in insufficient effect to counteract IL-1-induced subacromial synovitis in the disease.

We examined cells that expressed IL-1ß and IL-1ra protein by immunohistochemistry. Cells immunoreactive to IL-1 and IL-1ra have been identified in the synovial lining to sublining layers in osteoarthritis and rheumatoid arthritis [25]. Immunohistochemical analysis in the present study demonstrated a similar localization of positive signals for IL-1ß and IL-1ra (synovial lining and sublining cells). Combined together, these findings indicate the consistency of localization of cells producing these cytokines at the protein level.

Because both IL-1ra proteins are identical except that icIL-1ra lacks the signal sequence, which is replaced by a seven-residue extension at the N-terminus of the protein [11, 26], conventional immunohistochemistry cannot differentiate cells producing these cytokines. Using the in situ RT–PCR technique, we were able to demonstrate the localization of sIL-1ra mRNA in the sublining cells, while icIL-1ra mRNA was preferentially localized in the synovial lining cells. To our knowledge, no previous studies have demonstrated differences in the localization of sIL-1ra and icIL-1ra mRNA-producing cells in situ.

The differential localization of IL-1ra mRNAs in this study is noteworthy. Our RT–PCR analysis also demonstrated that relative to sIL-1ra mRNA, icIL-1ra mRNA is relatively up-regulated with higher expression levels of IL-1ß mRNA. In situ RT–PCR demonstrated that synovial lining cells preferentially produce icIL-1ra mRNA, while synovial sublining cells produce sIL-1ra mRNA. Relative up-regulation of icIL-1ra contributes to the inefficiency of counteracting IL-1 biological behaviour [23, 24]. These results suggest a different inflammatory response between synovial lining and sublining cells in the SAB, and that up-regulation of icIL-1ra mRNA production by synovial lining cells provides a disadvantage to counteract against IL-1-induced subacromial synovitis in rotator cuff diseases.

Unfortunately, we could not obtain synovial specimens as normal controls, such as from a cadaver. In our previous study, it was disclosed that the SAB in anterior instability without subacromial impingement is almost identical to normal synovium and use of the bursal synovium was suggested as appropriate for control specimens; in anterior instability of the shoulder, the expression levels of IL-1ß mRNA of the SAB were much less pronounced than those of the glenohumeral joint and the histological findings revealed no inflammatory reactions in the bursa, being similar to normal synovium [17]. Although we believe that the use of the SAB with anterior instability would be proper as base values, this point could be a limitation of this study.

This study demonstrated that mRNA expression levels of IL-1ß, sIL-1ra and icIL-1ra in the SAB were correlated with the degree of shoulder pain in patients with rotator cuff diseases, and that the expression of icIL-1ra mRNA in synovial lining cells is relatively up-regulated compared with that of sIL-1ra in sublining cells, in proportion to the overexpression of IL-1ß mRNA produced by both types of synovial cells. Based on these findings, we propose that the differential regulation of the two forms of IL-1ra in synovial cells in the SAB may play an important role in shoulder pain in patients with rotator cuff diseases.

In conclusion, we demonstrated in the present study that in subacromial synovitis of rotator cuff diseases, the expression of icIL-1ra mRNA in synovial lining cells is relatively up-regulated compared with that of sIL-1ra in sublining cells, in proportion to the overexpression of IL-1ß mRNA produced by both types of synovial cells. Based on these findings, we suggest that the differential regulation of the two forms of IL-1ra in synovial cells in the SAB may play an important role in shoulder pain in rotator cuff diseases, regulating IL-1-induced subacromial synovitis.


   Acknowledgments
 
We thank Mr Yuichi Tada, Dr Johbu Itoh and Miss Kyoko Murata for their technical assistance. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture (MN, 06670206), (C-2, 08671694), and by Tokai University School of Medicine Research Aid (MN, YU, HY).


   Notes
 
Correspondence to: M. Gotoh, Department of Orthopaedic Surgery, Kurume University School of Medicine, Asahi-machi 67, Kurume, Fukuoka, 830-0011, Japan Back


   References
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 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 19 October 2000; Accepted 2 April 2001


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