Clinical Efficacy of Nasal Screening and Methicillin-Resistant Staphylococcusaureus Decolonization in Total Hip Arthroplasty without Chlorhexidine Soap or Vancomycin.

Purpose: Nasal colonization with methicillin-resistant Staphylococcus aureus (MRSA) is a known risk factor for periprosthetic joint infection (PJI). In our facility, preoperative prophylaxis with mupirocin without the chlorhexidine soap scrub or vancomycin was consistently implemented for more than 15 years. This study aimed to evaluate the current screening and treatment of intranasal MRSA colonization in our elective primary THA patient population. Methods: All patients who underwent primary THA between April 2011, and March 2021 were included in this analysis. All patients were screened preoperatively for nasal MRSA approximately 1 month before surgery. Patients with nasal MRSA contamination are treated with topical mupirocin to eradicate the bacteria before surgery. The patients were examined again approximately two weeks before surgery. We evaluated the current screening and treatment of intranasal colonization with MRSA in our elective primary total hip arthroplasty (THA) patient population. Results: Out of 6251 patients, 106 (1.7%) had nasal MRSA contamination. The bacteria were not eradicated in three (3.6%) patients at the second screening. Twenty-two joints (0.35%) out of the 6251 had deep infections. Only 1 patient out of the 106 MRSA nasal carriers suffered from PJI. Twenty-one of the 6145 non-carriers had PJI. The difference between the prevalence of nasal MRSA contamination and the incidence of deep infections was not statistically significant. Conclusion: Our findings suggest that screening of all patients for nasal MRSA before THA followed by mupirocin calcium treatment if needed is sufficient PJI prophylaxis.

Denosumab prevented periprosthetic bone resorption better than risedronate after total hip arthroplasty.

INTRODUCTION: Periprosthetic fracture caused by periprosthetic bone loss is an important concern in total hip arthroplasty (THA). Denosumab has been approved for postmenopausal women with osteoporosis who are at high risk of fracture. In this randomized controlled trial, we compared the effects of denosumab and risedronate on periprosthetic bone mineral density (BMD) after THA. MATERIALS AND METHODS: The current study analyzed 108 patients who were scheduled to have THA. For 2 years, the patients were randomly assigned to the following two treatment groups: denosumab (60 mg subcutaneously every 6 months) or risedronate (17.5 mg oral weekly). The BMD changes in all Gruen zones and bone turnover markers were measured at the 5th postoperative day (baseline) and 6, 12, 18, and 24 months postoperatively. RESULTS: The mean BMD in zones 1, 2, 6, and 7 was significantly higher with denosumab all administration at all postoperative time points compared to the risedronate group. The mean percentage changes in the BMD in these zones from baseline to 24 months postoperatively were + 11.9, + 2.9, + 8.1, and + 5.9% with denosumab group and - 9.6% -3.6, - 2.3, and - 19.2% with risedronate, respectively. The osteoclastic marker, tartrate-resistant acid phosphatase-5b (TRACP-5b), was significantly lower in the denosumab group compared to the risedronate group by 2 months. CONCLUSION: Denosumab is more effective in preventing periprosthetic bone resorption than risedronate in the proximal femur. It also increased BMD around the stem implant following THA.

Effects of perioperative exercise therapy combined with nutritional supplementation on functional recovery after fast-track total hip arthroplasty.

BACKGROUND: The combination of exercise therapy combined with nutritional supplementation (Nutr) is widely used for frail or sarcopenic older persons. However, the effects of Nutr in elderly patients after fast-track total hip arthroplasty (THA) are unknown. This study examined the effects of perioperative Nutr on muscle strength, functional performance, and quality of life (QOL) in frail elderly women after fast-track THA. METHODS: A total of 58 frail elderly women aged 65-80 years scheduled for unilateral primary THA were randomly allocated to two groups: the physical exercise (Ex) combined with Nutr (Ex + Nutr; n = 29) group, and the Ex alone (Ex; n = 29) group. Protein and vitamin D supplements were provided daily from 4 weeks preoperatively to 8 weeks postoperatively (12 weeks) to the patients in the Ex + Nutr group, whereas the Ex group did not receive any supplements. Surgery and postoperative rehabilitation programmes during intervention were identical in both groups. Hip abductor and knee extensor muscle strength, functional performance (Timed Up & Go test, Harris Hip Score), and QOL (Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire) were assessed at baseline and at 12 weeks (8 weeks postoperatively). RESULTS: After the intervention, hip abductor muscle strength on the contralateral leg and knee extensor muscle strength on both sides significantly improved in the Ex + Nutr group compared to the Ex group (p = 0.03, 0.01, and 0.01, respectively). However, hip abductor muscle strength on the operated side did not differ significantly between the groups (p = 0.23). There were no significant differences in functional performance and QOL. CONCLUSION: Ex + Nutr does not have an additional effect on the improvement of hip abductor strength, functional performance, and QOL compared to Ex alone after fast-track THA. However, significant improvements were observed in the strength of some muscles after fast-track THA. TRIAL REGISTRATION: UMIN 000042964. THE IRB APPROVAL: This study was approved by the Mirai Iryo Reesearch Center (approval number TGE1602-115).

Adverse Local Tissue Reaction and Late-Onset Eosinophilic Gastroenteritis After Primary Total Hip Arthroplasty: A Case Report.

CASE: A 67-year-old woman suffered from chronic diarrhea at 10 years after right total hip arthroplasty. She also had a pseudotumor caused by an adverse local tissue reaction (ALTR) in her right pelvis. We performed revision arthroplasty, in part because we suspected the diarrhea may have been associated with the intrapelvic pseudotumor. She was later diagnosed with eosinophilic gastroenteritis (EGE). CONCLUSION: Although these two diseases were thought be be related through a similar immune reaction, our patient's clinical course suggests that the ALTR and EGE were independent events.

Clinical efficacy of risk-stratified prophylaxis with low-dose aspirin for the management of symptomatic venous thromboembolism after total hip arthroplasty.

BACKGROUND: Pulmonary thromboembolism (PTE) and deep vein thrombosis (DVT) are serious complications after total hip arthroplasty (THA). Aspirin has been considered a safe and cost-effective prophylaxis for venous thromboembolism (VTE), and there have been some reports about the incidence of PTE (0%-0.57%) and DVT (0.1%-0.35%) with low-dose aspirin for prophylaxis after THA. The aim of this study was to investigate the incidence of postoperative symptomatic VTE in our hospital and to evaluate the clinical efficacy of our prophylactic regimen. PATIENT AND METHODS: We retrospectively reviewed the medical records of consecutive patients who underwent THA in our hospital between 2011 and 2016. A total of 3295 hips (male: 337 patients, 365 hips; female: 2527 patients, 2930 hips) were enrolled in this study. Patients were divided into low-risk and high-risk groups. Low-risk patients were administered aspirin (100 mg/day) for 28 days postoperatively. High-risk patients, such as those diagnosed with obesity and/or with a history of VTE, received anticoagulants (enoxaparin or edoxaban) for 5 days postoperatively, followed by a dose of aspirin for 28 days. Based on our criteria, 218 of 3295 hips were considered high risk. RESULTS: No VTE-related mortality was observed. One patient developed symptomatic PTE, and one patient developed symptomatic DVT. Both were successfully treated. Postoperative fatal bleeding or bleeding from any organ such as gastrointestinal and cerebral hemorrhage were not observed. A low incidence (0.03%) was observed for symptomatic DVT and PTE. CONCLUSIONS: This study demonstrated that the hospital's risk-stratified protocol using low-dose aspirin or anticoagulants was clinically effective in preventing symptomatic VTE. These results were considerably better than those reported from Western countries. However, all patients in this study were the Japanese. It was unclear whether similar results were given to non-Japanese patients. Therefore, this protocol needs severe carefulness to be applied to non-Japanese populations.

Additional intraarticular tranexamic acid further reduced postoperative blood loss compared to intravenous and topical bathed tranexamic acid in total hip arthroplasty: a retrospective sequential series study.

BACKGROUND: Topical tranexamic acid (TXA) administration has been described to be effective in decreasing blood loss in total hip arthroplasty (THA). The aim of this retrospective study was to evaluate whether topical intraarticular TXA administration in addition to intravenous (IV) and topical bathed TXA further reduces blood loss in THA patients. STUDY DESIGN AND METHODS: Four-hundred patients were enrolled in this sequential series study with two different phases during four different time periods. Patients were divided based on TXA usage and route of administration: those with and without IV TXA (IVTA-I and no-IVTA groups, respectively) and those with and without intraarticular TXA (TITA and IVTA-II groups, respectively). Both IVTA-II and TITA groups had IV TXA, and all four groups used topical bathed TXA. These four groups had 100 cases each. The primary outcomes were evaluated with total blood loss and postoperative hemoglobin level. RESULTS: The total blood loss was 1106 and 875 mL in the no-IVTA and IVTA-I groups, respectively (p < 0.05). Postoperative Hb was 10.9 and 11.51 g/dL in the no-IVTA and IVTA-I groups, respectively (p < 0.05). Total blood loss was 813 and 646 mL in the IVTA-II and TITA groups, respectively (p < 0.05). Intraarticular with IV and bathed TXA administration was more effective than IV and bathed TXA in reducing blood loss. CONCLUSION: This study suggests that the combined administration of topical intraarticular, bathed, and IV TXA was effective in reducing blood loss in THA patients.

Tocilizumab, a humanized anti-IL-6R antibody, as an emerging therapeutic option for rheumatoid arthritis: molecular and cellular mechanistic insights.

Pro-inflammatory cytokines play a major role in the initiation and maintenance of joint inflammation and destruction in rheumatoid arthritis (RA). The therapeutic success of biologics targeting tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1) and interleukin (IL)-6 receptor (IL-6R) has broadened the treatment options for RA. These agents have potential overlapping and discriminating biologic effects, as well as different pharmacological features. Tocilizumab (TCZ) is a humanized monoclonal antibody that binds and neutralizes IL-6R, resulting in the inhibition of various IL-6-mediated biological activities, including inflammation-related, immunomodulatory and tissue/matrix remodelling effects. Randomized, double-blind, controlled phase III studies and a number of early clinical observational studies have shown that treatment with TCZ results in rapid and sustained improvement in the signs and symptoms of RA among different patient populations. These studies have established the efficacy and safety of TCZ. Here, we review the pleiotropic functions of IL-6 and how it impinges on many aspects of RA pathogenesis, and highlight the clinical experience to date with TCZ as an emerging new treatment option for RA.

Anti-interleukin-6 receptor antibody prevents systemic bone mass loss via reducing the number of osteoclast precursors in bone marrow in a collagen-induced arthritis model.

Systemic bone loss is a hallmark of rheumatoid arthritis (RA). Inflammatory cytokines such as interleukin (IL)-6 promote bone resorption by osteoclasts. Sphingosine-1-phosphate (S1P) controls the migration of osteoclast precursor cells (OCPs) between the blood and bone marrow, in part via S1P receptors (S1PR1 and S1PR2) expressed on the surface of OCPs. OCPs (CD11b(+) Gr-1(low+med) ) isolated from bone marrow of DBA/1J mice were stimulated with IL-6. S1P-directed chemotaxis of OCPs was evaluated using a transwell plate. mRNA expression of S1PR1 and S1PR2 was measured. DBA/1J mice were immunized with bovine type II collagen (days 0 and 21) and anti-mouse IL-6 receptor antibody (MR16-1) was administered on days 0 and/or 21. Trabecular bone volume was analysed using micro-computed tomography. The percentage of OCPs in tibial bone marrow and S1PR1 and S1PR2 mRNA expression in OCPs were measured. IL-6 stimulation significantly decreased S1P-directed chemotaxis of OCPs. IL-6 induced S1PR2 mRNA expression, but not S1PR1 mRNA expression, in OCPs. Bone volume was significantly lower in arthritic mice than in non-arthritic control mice on day 35. Treatment of immunized mice with MR16-1 significantly inhibited bone loss. In MR16-1-treated mice, the percentage of OCPs and expression of S1PR2 mRNA was each decreased compared with arthritic mice on day 14, but not on day 35. IL-6 increased the number of OCPs in tibial bone marrow via up-regulating S1PR2, thus playing a crucial role in systemic bone loss induced by inflammation.

Combination treatment with eldecalcitol (ED-71) and raloxifene improves bone mechanical strength by suppressing bone turnover and increasing bone mineral density in ovariectomized rats.

The aim of this study was to investigate the effect of combination treatment with eldecalcitol (ELD) and raloxifene (RAL) on bone turnover, bone mineral density (BMD), and bone strength. Eight-month-old rats were ovariectomized (OVX) or sham operated, and divided into five groups (Sham, OVX+vehicle, OVX+RAL, OVX+ELD and OVX+ELD+RAL). ELD (7.5 ng/kg) and RAL (0.3mg/kg) were orally administered alone or in combination daily. Urinary deoxypyridinoline (DPD) levels were measured after 4, 8, and 12 weeks of treatment. After 12 weeks of treatment, BMD and mechanical properties of the lumbar spine and femur were assessed, and bone histomorphometry was performed. Urinary DPD levels in all the treatment groups were significantly decreased compared with the OVX+vehicle group. At 4 weeks of treatment, urinary DPD level of the combination group was significantly lower than that of either monotherapy group. The reduction in the BMD of the lumbar spine and femur by OVX was significantly prevented in all the treatment groups, and the BMD in the combination group was significantly higher than that in either monotherapy group. The ultimate load and work to failure of the fifth lumbar vertebra were significantly improved only by the combination treatment. The femoral midshaft ultimate load was significantly increased in the OVX+ELD group and the combination group, and the femoral midshaft work to failure was increased only in the combination group. Bone histomorphometric analysis using the third lumbar vertebra revealed that osteoblast surface (Ob.S/BS), osteoclast surface (Oc.S/BS) and osteoclast number (N.Oc/BS) significantly decreased in all treatment groups, and osteoid surface (OS/BS) and bone formation rate (BFR/BS) significantly decreased in the ELD-treated and combination groups. The values of Ob.S/BS and OS/BS in the combination group were lower than those in either of the monotherapy groups. The bone formation parameters in the combination group were not reduced to below levels of the sham-operated control, suggesting that the combination therapy with ELD and RAL may not cause oversuppression of bone turnover. These results indicated that the combination treatment with ELD and RAL might be a beneficial therapy with respect to their combined effects of enhancing the mechanical properties of trabecular and cortical bone by suppressing bone turnover and increasing BMD more than either monotherapy.

Murine tumor necrosis factor α-induced adipose-related protein (tumor necrosis factor α-induced protein 9) deficiency leads to arthritis via interleukin-6 overproduction with enhanced NF-κB, STAT-3 signaling, and dysregulated apoptosis of macrophages.

OBJECTIVE: To elucidate the role of tumor necrosis factor α-induced adipose-related protein (TIARP; or tumor necrosis factor α-induced protein 9 [TNFAIP-9]) in the development and pathogenesis of arthritis. METHODS: We generated TIARP-deficient (TIARP(-/-) ) mice and investigated several organs in aged mice. Peritoneal macrophages were collected and cultured with lipopolysaccharide (LPS) and TNFα, and then the production of cytokines and subsequent NF-κB signal transduction were analyzed. We also examined the susceptibility of young TIARP(-/-) mice to collagen-induced arthritis (CIA). Draining lymph nodes and splenocytes were isolated and cultured, and serum levels of anti-type II collagen (anti-CII) antibodies, interleukin-6 (IL-6), and TNFα on day 60 were measured. We further investigated the effects of anti-IL-6 receptor monoclonal antibody (mAb) on the development of arthritis in TIARP(-/-) mice. IL-6/STAT-3 signaling was also analyzed using TIARP(-/-) macrophages. RESULTS: TIARP(-/-) mice developed spontaneous enthesitis and synovitis, had high serum levels of IL-6, had increased CD11b+ cell counts in the spleen, and showed enhanced LPS- and TNFα-induced IL-6 expression in macrophages. Sustained degradation of IκBα with dysregulated apoptosis was also noted in TIARP(-/-) macrophages. CIA was clearly exacerbated in TIARP(-/-) mice, accompanied by marked neutrophil and macrophage infiltration in joints. The levels of anti-CII antibodies in serum were unchanged, whereas autoreactive Th1 cell and Th17 cell responses were higher in TIARP(-/-) mice. Treatment with anti-IL-6 receptor mAb prevented the development of CIA in TIARP(-/-) mice, and TIARP(-/-) macrophages showed increased IL-6-induced STAT-3 phosphorylation. CONCLUSION: These findings suggest that TIARP acts as a negative regulator of arthritis by suppressing IL-6 production, its signaling and TNFα-induced NF-κB signaling, resulting in enhanced apoptosis in macrophages.

Blockade of IL-6 and TNF-α inhibited oxLDL-induced production of MCP-1 via scavenger receptor induction.

In chronic inflammatory diseases, cardiovascular disease risk is increased and is the main cause of increased mortality. Oxidized LDL (oxLDL) and scavenger receptors participate in atherogenesis. Using human arterial endothelial cells (HAECs), we evaluated the effect of IL-6 and TNF-α on the expression of scavenger receptors. IL-6 induced expression of SR-A mRNA and TNF-α induced both SR-A and LOX-1 mRNA. Both did induce either CD36 or CD68. To assess the function of scavenger receptors, MCP-1 production by oxLDL from cytokine-pretreated HAEC was examined. In accordance with scavenger receptor expression, oxLDL-induced MCP-1 production was increased in IL-6- or TNF-α-pretreatment. Serum from rheumatoid arthritis patients but not from healthy subjects increased mRNA expressions of SR-A, LOX-1 and CD36 in HAEC. SR-A expression was inhibited by both anti-IL-6 receptor antibody (α-IL-6R Ab) and TNF-α receptor (p75)-Fc (TNFR-Fc) and LOX-1 expression was inhibited by TNFR-Fc. CD36 expression was affected by neither. Serum from rheumatoid arthritis patients augmented oxLDL-induced MCP-1 production. Both α-IL-6R Ab and TNFR-Fc partially inhibited this MCP-1 production. In conclusion, our results strongly support that blocking therapy of IL-6 and TNF-α might be beneficial to reduce atherosclerosis risk in chronic inflammatory diseases.

Interleukin-6 regulates anti-arthritic effect of methotrexate via reduction of SLC19A1 expression in a mouse arthritis model.

INTRODUCTION: Methotrexate (MTX) enters cells via the reduced folate carrier SLC19A1, suggesting that SLC19A1 is associated with the efficacy of MTX. We here examined the relationship between the efficacy of MTX and the expression of SLC19A1 in glucose 6-phosphate isomerase (GPI)-induced arthritis. We found that interleukin-6 (IL-6) regulated the expression of SLC19A1, so we studied the effect of a combination of MTX and anti-mouse IL-6 receptor antibody (MR16-1). METHODS: GPI-induced arthritis was induced by intradermal immunization with recombinant GPI. MTX was given from the first day of immunization. Mice were injected once with MR16-1 10 days after immunization. The levels of SLC19A1 mRNA in whole hind limbs and immune cells were measured. Synovial cells from arthritic mice were cultured with cytokines, and cell proliferation and gene expressions were measured. RESULTS: MTX inhibited the development of GPI-induced arthritis; however, the efficacy of MTX gradually diminished. SLC19A1 expression in immunized mice with arthritis was lower than in intact mice; moreover, SLC19A1 expression in arthritic mice was further decreased when they were treated with MTX. IL-6 was highly expressed in whole hind limbs of arthritic mice. In an in vitro study using synovial cells from arthritic mice, IL-6 + soluble IL-6 receptor (sIL-6R) weakened the anti-proliferative effect of MTX and reduced SLC19A1 expression. Finally, although MR16-1 did not improve arthritis at all when administered on day 10, MTX in combination with MR16-1 more potently reduced the development of arthritis than did MTX alone. When used in combination with MTX, MR16-1 apparently reversed the decrease in SLC19A1 induced by MTX alone. CONCLUSIONS: In the present study, we demonstrated for the first time that IL-6 reduced the efficacy of MTX by decreasing the expression of SLC19A1, which is important for MTX uptake into cells.

Adiponectin induces CCL20 expression synergistically with IL-6 and TNF-α in THP-1 macrophages.

Adiponectin (Ad) is an adipokine secreted from adipocytes. It is reported that Ad has many biological activities. However, its influence on inflammation is controversial. In the present study, we examined the influence of Ad on production of CCL20 from THP-1 macrophages. THP-1 macrophages were prepared from THP-1 monocytes by PMA treatment. THP-1 macrophages were cultured for 24h with Ad, IL-6, or TNF-α alone or with combinations of Ad and cytokines. CCL20 mRNA expression was then determined by real-time PCR. Full-length Ad (fAd) slightly but significantly induced CCL20 mRNA expression, and interestingly, co-stimulation with fAd and IL-6 or with fAd and TNF-α synergistically increased the expression of CCL20 mRNA. We explored the mechanism behind the synergistic effect of fAd and these cytokines. fAd did not affect the expression of receptors for IL-6 and TNF, and IL-6 and TNF-α did not increase the expression of the receptor for Ad in THP-1 macrophages. The increased expression of CCL20 by fAd is much higher in THP-1 macrophages compared with THP-1 monocytes. Furthermore, MMP-12 production was increased by IL-6 and TNF-α in THP-1 macrophages but it was not detectable in THP-1 monocytes. Treatment of fAd with MMP-12 induced globular Ad (gAd), and the expression of CCL20 in THP-1 macrophages was increased more potently by gAd than by fAd. MMP inhibitor (UK370106) inhibited the expression of CCL20 induced by co-stimulation with fAd and IL-6 or TNF-α. In conclusion, gAd played an important role in CCL20 expression, and MMP-12 induced by IL-6 or TNF-α was involved in the synergistic effect of fAd and cytokines.

Atherogenic effects of TNF-α and IL-6 via up-regulation of scavenger receptors.

Patients with chronic inflammatory disorders such as rheumatoid arthritis (RA) have a high risk of developing cardiovascular disease. We evaluated the effects of TNF-α and IL-6 on foam cell formation, a pivotal process in atherogenesis. Accumulation of intracellular oxidized LDL (oxLDL) was induced when THP-1/macrophages were stimulated with TNF-α or IL-6. TNF-α induced the expressions of scavenger receptors SR-A and LOX-1, and IL-6 induced SR-A expression. Inhibition of the NF-κB signaling markedly decreased TNF-α-induced foam cell formation and SR-A expression. Serum from RA patients, but not healthy subjects, induced foam cell formation, which was partially reversed by either IL-6 or TNF-α blockade in conjunction with inhibiting the induction of scavenger receptors. The present study clearly showed that in patients with chronic inflammation mediated by TNF-α and IL-6, these cytokines are directly implicated in atherosclerotic plaque formation.

Combination therapy with eldecalcitol and alendronate has therapeutic advantages over monotherapy by improving bone strength.

Eldecalcitol (ED-71), a 2ß-hydroxypropyloxy derivative of 1α,25(OH)(2)D(3), inhibits bone resorption more potently than does alfacalcidol while maintaining osteoblastic function in an estrogen-deficient, high-turnover osteoporosis rat model. Alendronate (ALN) has been reported to increase bone mass by suppressing bone resorption mainly by inducing apoptosis of osteoclasts. The aim of this study was to clarify the combination effect of ED-71 and ALN on bone loss in ovariectomized rats. Wistar-Imamichi rats (32weeks old) were ovariectomized and randomly assigned to 10 groups (n=9-11); 11 rats were sham-operated. Rats were orally administered either vehicle alone, ALN (0.05, 0.2mg/kg), ED-71 (0.015, 0.03µg/kg), or a combination of ALN and ED-71. The treatment started 2weeks after surgery and continued for 12weeks. ED-71 significantly increased calcium and phosphorus in serum and urine; however, the mean values were within the normal range. Bone mineral density (BMD) and maximum load in both the lumbar spine and femur significantly increased with ED-71 monotherapy, and showed a tendency to increase with ALN monotherapy. Compared with ALN monotherapy, the combination of ALN and ED-71 significantly increased BMD and maximum load in both the lumbar spine and femur, suggesting that the combination therapy is more beneficial than ALN monotherapy in this protocol. The combination treatment had an additive suppressive effect on eroded surface and osteoclast number, with the suppressive effect more potent than either ALN or ED-71 monotherapy. Moreover, the combination therapy partially counteracted the suppressive effects of ALN on bone formation and on the histomorphometric indices of osteoblast number and activity. Interestingly, ALN had no effect on the anabolic action of ED-71. In conclusion, the combination therapy of ALN and ED-71 has therapeutic advantages over ALN monotherapy in terms of improving bone mechanical strength without excessive suppression of bone turnover.

IL-6/IL-6 receptor system and its role in physiological and pathological conditions.

IL (interleukin)-6, which was originally identified as a B-cell differentiation factor, is a multifunctional cytokine that regulates the immune response, haemopoiesis, the acute phase response and inflammation. IL-6 is produced by various types of cell and influences various cell types, and has multiple biological activities through its unique receptor system. IL-6 exerts its biological activities through two molecules: IL-6R (IL-6 receptor) and gp130. When IL-6 binds to mIL-6R (membrane-bound form of IL-6R), homodimerization of gp130 is induced and a high-affinity functional receptor complex of IL-6, IL-6R and gp130 is formed. Interestingly, sIL-6R (soluble form of IL-6R) also binds with IL-6, and the IL-6-sIL-6R complex can then form a complex with gp130. The homodimerization of receptor complex activates JAKs (Janus kinases) that then phosphorylate tyrosine residues in the cytoplasmic domain of gp130. The gp130-mediated JAK activation by IL-6 triggers two main signalling pathways: the gp130 Tyr759-derived SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase-2)/ERK (extracellular-signal-regulated kinase) MAPK (mitogen-activated protein kinase) pathway and the gp130 YXXQ-mediated JAK/STAT (signal transducer and activator of transcription) pathway. Increased IL-6 levels are observed in several human inflammatory diseases, such as rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis. IL-6 is also critically involved in experimentally induced autoimmune diseases. All clinical findings and animal models suggest that IL-6 plays a number of critical roles in the pathogenesis of autoimmune diseases. In the present review, we first summarize the IL-6/IL-6R system and IL-6 signal transduction, and then go on to discuss the physiological and pathological roles of IL-6.

The roles of interleukin-6 in the pathogenesis of rheumatoid arthritis.

Several clinical studies have demonstrated that the humanized anti-interleukin-6 (IL-6) receptor antibody tocilizumab (TCZ) improves clinical symptoms and prevents progression of joint destruction in rheumatoid arthritis (RA). However, the precise mechanism by which IL-6 blockade leads to the improvement of RA is not well understood. IL-6 promotes synovitis by inducing neovascularization, infiltration of inflammatory cells, and synovial hyperplasia. IL-6 causes bone resorption by inducing osteoclast formation via the induction of RANKL in synovial cells, and cartilage degeneration by producing matrix metalloproteinases (MMPs) in synovial cells and chondrocytes. Moreover, IL-6 is involved in autoimmunity by altering the balance between T(h)17 cells and T(reg). IL-6 also acts on changing lipid concentrations in blood and on inducing the production of hepcidin which causes iron-deficient anemia. In conclusion, IL-6 is a major player in the pathogenesis of RA, and current evidence indicates that the blockade of IL-6 is a beneficial therapy for RA patients.

Anti-IL-6 receptor antibody causes less promotion of tuberculosis infection than anti-TNF-α antibody in mice.

Objective. Our aim was to investigate the effects of IL-6 blockade on the progression of Mycobacterium tuberculosis (TB) and compare them with those of TNF-α blockade in mice. Methods. Mice were intravenously infected with TB and injected with antibodies. Survival was monitored and histological and immunological studies were carried out. Results. All anti-IL-6R Ab-treated mice and 8 of 10 control mice survived until sacrificed 224 days after TB challenge, whereas anti-TNF-α Ab-treated mice all died between 120 and 181 days. Anti-IL-6R Ab-treated mice exhibited no significant differences in TB CFU in organs, including the lungs, and no deterioration in histopathology compared to control mice at 4 weeks. In contrast, anti-TNF-α Ab-treated mice exhibited increased TB CFU and greater progression of histopathological findings in organs than control mice. Spleen cells from anti-TNF-α Ab-treated mice had decreased antigen-specific response in IFN-γ release and proliferation assays. The results in anti-IL-6R Ab-treated mice suggest that spleen cell responses were decreased to a lesser degree. Similar results were obtained in IL-6 knockout (KO) mice, compared with TNF receptor 1 (TNFR1) KO and TNFR1/IL-6 double KO (DKO) mice. Conclusion. IL-6R blockade promotes the progression of TB infection in mice far less than TNF-α blockade.

Instability of Foxp3 expression limits the ability of induced regulatory T cells to mitigate graft versus host disease.

PURPOSE: Graft versus host disease (GVHD) is the major complication of allogeneic bone marrow transplantation (BMT) and limits the therapeutic efficacy of this modality. Although the role of natural T-regulatory cells (nTreg) in attenuating GVHD has been extensively examined, the ability of induced T-regulatory cells (iTreg) to mitigate GVHD is unknown. The purpose of this study was to examine the ability of in vitro and in vivo iTregs to abrogate GVHD. EXPERIMENTAL DESIGN: We examined the ability of in vitro differentiated and in vivo iTregs to reduce the severity of GVHD in a clinically relevant mouse model of BMT. The effect of blockade of interleukin (IL) 6 signaling on the efficacy of these Treg populations was also studied. RESULTS: In vitro differentiated iTregs fail to protect mice from lethal GVHD even when administered at high Treg:effector T-cell ratios. Lack of GVHD protection was associated with loss of Foxp3 expression and in vivo reversion of these cells to a proinflammatory phenotype characterized by secretion of IFN-γ. Phenotypic reversion could not be abrogated by blockade of IL-6 signaling or by in vitro exposure of iTregs to all-trans retinoic acid. In contrast, the in vivo induction of iTregs was significantly augmented by IL-6 blockade and this resulted in reduced GVHD. CONCLUSION: Instability of Foxp3 expression limits the utility of adoptively transferred iTregs as a source of cellular therapy for the abrogation of GVHD. Blockade of IL-6 signaling augments the ability of in vivo iTregs to prevent GVHD but has no effect on in vitro differentiated iTregs.