Serum IL-23 significantly decreased in obese patients with psoriatic arthritis six months after a structured weight loss intervention.

INTRODUCTION: Patients with psoriatic arthritis (PsA) are frequently obese. We have previously shown decreased disease activity in patients with PsA with a body mass index (BMI) ≥ 33 kg/m2 following weight loss treatment with Very Low Energy Diet (VLED), resulting in a median weight loss of 18.6% at six months (M6) after baseline (BL). In this study we assessed the effects of VLED on cytokines and adipokines at M6 in the same patients with PsA and controls (matched on sex, age and weight). METHODS: VLED (640 kcal/day) during 12 or 16 weeks, depending on BL BMI < 40 or ≥ 40 kg/m2, was taken and followed by an energy-restricted diet. Cytokines and adipokines were measured with Magnetic Luminex Assays at BL and M6. RESULTS: Serum interleukin (IL)-23, (median (interquartile range) 0.40 (0.17-0.54) ng/mL vs. 0.18 (0.10-0.30) ng/mL, p < 0.001) and leptin (26.28 (14.35-48.73) ng/mL vs. 9.25 (4.40-16.24) ng/mL, p < 0.001) was significantly decreased in patients with PsA. Serum total (tot)-adiponectin and high molecular weight (HMW) adiponectin increased significantly. Similar findings were found in controls. Also, in patients with PsA, ∆BMI was positively correlated with ∆IL-23 (rS = 0.671, p < 0.001). In addition, significant positive correlations were found between ΔBMI and ΔDisease Activity Score (DAS28CRP), ΔCRP, Δtumor necrosis factor (TNF)-α, ΔIL-13, ∆IL-17 and Δleptin, and negative correlations between ΔBMI and Δtot-adiponectin. CONCLUSIONS: Weight loss was associated with decreased levels of leptin and cytokines, in particular IL-23. These findings may partly explain the anti-inflammatory effect of weight reduction in PsA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02917434, registered on September 21, 2016, retrospectively registered.

The lived experience of the early postoperative period after colorectal cancer surgery.

Colorectal cancer is one of the most common cancer diagnoses and undergoing colorectal cancer surgery is reported to be associated with physical symptoms and psychological reactions. Social support is described as important during the postoperative period. The purpose of this paper was to describe how patients experience the early postoperative period after colorectal cancer surgery. Interviews according a phenomenological approach were performed with 13 adult participants, within 1 week after discharge from hospital. Data were collected from August 2006 to February 2007. Analysis of the interview transcripts was conducted according to Giorgi. The essence of the phenomenon was to regain control over ones body in the early postoperative period after colorectal cancer surgery. Lack of control, fear of wound and anastomosis rupture, insecurity according to complications was prominent findings. When caring for these patients it is a challenge to be sensitive, encourage and promote patients to express their feelings and needs. One possibility to empower the patients and give support could be a follow up phone call within a week after discharge.

Influence of oestrogen receptor alpha and beta on the immune system in aged female mice.

Oestrogen has a dichotomous effect on the immune system. T and B lymphopoiesis in thymus and bone marrow is suppressed, whereas antibody production is stimulated by oestrogen. In this study the importance of the oestrogen receptors (ER) ER-alpha and ER-beta in the aged immune system was investigated in 18 months old-wild type (WT), ER-alpha (ERKO), ER-beta (BERKO) and double ER-alpha and ER-beta (DERKO) knock-out mice, and compared with 4 months old WT mice. Cell phenotypes in bone marrow, spleen and thymus, and the frequency of immunoglobulin (Ig) spot forming cells (SFC) were determined. We show here that the 17-beta-oestradiol (E2)-induced downregulation of B lymphopoietic cells in bone marrow of young ovariectomized mice can be mediated through both ER-alpha and ER-beta. However, only ER-alpha is required for the age-related increased frequency of immunoglobulin M (IgM) SFC in the bone marrow, as well as for the increased production of interleukin-10 (IL-10) from cultured splenocytes in aged mice. Furthermore, increased age in WT mice resulted in lower levels of both pro- and pre-B cells but increased frequency of IgM SFC in the bone marrow, as well as increased frequency of both IgM and IgA SFC in the spleen. Results from this study provide valuable information regarding the specific functions of ER-alpha and ER-beta in the aged immune system.

Oestrogen receptor specificity in oestradiol-mediated effects on B lymphopoiesis and immunoglobulin production in male mice.

Oestrogen treatment down-regulates B lymphopoiesis in the bone marrow of mice. Meanwhile it up-regulates immunoglobulin production. To understand better the oestrogen action on bone marrow male mice lacking oestrogen receptor alpha (ERalpha; ERKO mice), lacking ERbeta (BERKO mice), lacking both receptors (DERKO mice) or wild-type (wt) littermates were castrated and treated for 2.5 weeks with 30 microg/kg 17beta-oestradiol (E2) or vehicle oil as controls. The B lymphopoiesis in the bone marrow was examined by flow cytometry and mature B-cell function was studied using an ELISPOT assay enumerating the B cells in bone marrow and spleen that were actively producing immunoglobulins. In wt mice the frequency of B-lymphopoietic (B220+) cells in the bone marrow decreased from 15% to 5% upon E2 treatment. In ERKO and BERKO mice significant reduction was seen but not of the same magnitude. In DERKO mice no reduction of B lymphopoiesis was seen. In addition, our results show that E2 mediated reduction of different steps in B lymphopoiesis require only ERalpha or both receptors. In wt and BERKO mice E2 treatment resulted in significantly increased levels of B cells actively producing immunoglobulin, while in ERKO and DERKO mice no such change was seen. Similar results were found in both bone marrow and spleen. In conclusion our results clearly show that both ERalpha and ERbeta are required for complete down-regulation of B lymphopoiesis while only ERalpha is needed to up-regulate immunoglobulin production in both bone marrow and spleen.

Raloxifene- and estradiol-mediated effects on uterus, bone and B lymphocytes in mice.

Raloxifene is a selective estrogen receptor modulator approved for the prevention of osteoporosis in postmenopausal women. It is selective by having estrogen-agonistic effects on bone, vessels and blood lipids while it is antagonistic on mammary and uterine tissue. Our aim was to study the agonistic and antagonistic properties of the raloxifene analogue LY117018 (LY) on uterus, bone, B lymphopoiesis and B cell function. Oophorectomized and sham-operated animals were treated with s.c. injections of equipotent anti-osteoporotic doses of 17beta-estradiol (E2) (0.1 mg/kg) or LY (3 mg/kg) or vehicle as controls. Effects on bone mineral density (BMD) were studied using peripheral quantitative computed tomography, uterine weight was examined, B lymphopoiesis was examined using flow cytometry and B cell function in bone marrow and spleen was studied by the use of an ELISPOT assay. E2 and LY had similar effects on BMD and bone marrow B lymphopoiesis, while LY had a clear antagonistic effect on endogenous estrogen in uterine tissue and no stimulating effect on the frequency of Ig-producing B cells in sham-operated animals. Our results are discussed in the context of estrogen receptor biology, relations between the immune system and bone metabolism and also with respect to the estrogen-mediated effects on rheumatic diseases.

Inosine monophosphate dehydrogenase (IMPDH) inhibition in vitro suppresses lymphocyte proliferation and the production of immunoglobulins, autoantibodies and cytokines in splenocytes from MRLlpr/lpr mice.

The aim of this study was to evaluate the effects of the immunomodulating drug mycophenolic acid (MPA) on splenocytes in an animal model of systemic lupus erythematosus (SLE), using MRLlpr/lpr mice. MPA reversibly inhibits inosine 5'-monophosphate dehydrogenase, an enzyme involved in the de novo guanosine synthesis. Splenocytes were treated with MPA (at 1 or 10 microM), and stimulated with either lipopolysaccharide (LPS; 10 microg/ml) or concanavalin A (ConA; 1.25 microg/ml). In blocking experiments, guanosine (100 microM) was added to the cultures to inhibit the effects of MPA. Lymphocyte proliferation, enumeration of immunoglobulin producing cells (using ELISPOT) and quantification of anti-double-stranded (ds) DNA antibodies, IFN-gamma and IL-10 (by ELISA) in supernatants were performed. In addition, cell viability was evaluated using propidium iodide and flow cytometry. We found that MPA-treated splenocytes had dramatically decreased mitogen-induced proliferation and number of immunoglobulin producing cells, down-regulated production of IFN-gamma, IL-10 and IgM anti-dsDNA antibodies. The viability of MPA-treated cells was also decreased. All of the effect modulated by MPA could be neutralized by the addition of guanosine. We conclude that MPA has potent immunomodulating effects on both B and T lymphocytes, modulating not only proliferation, but also the production of cytokines, immunoglobulins and autoantibodies.

Mycophenolate mofetil ameliorates perivascular T lymphocyte inflammation and reduces the double-negative T cell population in SLE-prone MRLlpr/lpr mice.

Effects on T lymphocyte mediated pathology, phenotypes, and functions in MRLlpr/lpr mice given mycophenolate mofetil (MMF) (100 mg/kg/day) via drinking water or controls given ip cyclophosphamide (CYC) injections (1.8 mg/mouse/week) or water were described. Both MMF and CYC treatment diminished kidney and large salivary gland perivascular cell infiltrates, reduced profoundly double-negative (DN) T cell frequencies, decreased total lymphocyte number in spleen, and increased in vitro proliferative response to Con A. IFN-gamma and IL-10 in supernatants from Con A stimulated spleen cells were augmented after MMF but not CYC treatment. MMF treatment increased whereas CYC reduced IL-12 in serum. Kidney expressions of IFN-gamma, IL-10, and IL-12 mRNA were unaffected by MMF but decreased by CYC. Our results demonstrate that MMF and CYC suppress perivascular T lymphocyte inflammation by reducing the DN T cell population and by amelioration of T cell function. The varying cytokine patterns suggest different mechanisms of the two drugs.

Beneficial effect of the inosine monophosphate dehydrogenase inhibitor mycophenolate mofetil on survival and severity of glomerulonephritis in systemic lupus erythematosus (SLE)-prone MRLlpr/lpr mice.

The aim of the present study was to evaluate the therapeutic effect of mycophenolate mofetil (MMF) on the course of disease in SLE-prone MRLlpr/lpr mice. Three-months-old mice displaying clinical symptoms of glomerulonephritis were given MMF (100 mg/kg per day) orally via the drinking water. Control mice received i.p. injections of cyclophosphamide (CYC) (1.8 mg/mouse per week) or saline. Survival, albuminuria and haematuria, immunoglobulin levels and anti-dsDNA antibodies in serum, frequencies of immunoglobulin-producing B lymphocytes and glomerular deposits of immunoglobulin and C3 were analysed. The results showed that MMF treatment significantly prolonged survival and reduced the occurrence of albuminuria and haematuria in MRLlpr/lpr mice. In addition, the number of immunoglobulin-producing B cells and serum levels of IgG and IgG anti-dsDNA antibodies were reduced after MMF and CYC treatment. MMF treatment significantly reduced the extent of deposition of C3 in glomeruli. We conclude that the reduced severity of glomerulonephritis following treatment of lupus-prone mice with MMF was as efficacious as that of CYC. These results warrant clinical trials of MMF in SLE patients with glomerulonephritis.