David C. Wilson

Follistatin-Like Protein-1 Is a Novel Proinflammatory Molecule

While analyzing gene expression in collagen-induced arthritis, we discovered that a poorly characterized gene, follistatin-like protein 1 (FSTL-1), is highly overexpressed in mouse paws during early arthritis, especially at the interface of synovial pannus and eroding bone. In this study, we show that FSTL-1 is a novel proinflammatory molecule with a previously unrecognized role in inflammation. Transfection of FSTL-1 into macrophages and fibroblasts leads to up-regulation of proinflammatory cytokines, including IL-1β, TNF-α, and IL-6. Overexpression of FSTL-1 in mouse paws by gene transfer results in severe paw swelling and arthritis.

Follistatin-Like Protein 1 Promotes Arthritis by Up-Regulating IFN-γ

Follistatin-like protein-1 (FSTL-1) is a poorly characterized protein that is up-regulated in the early stage of collagen-induced arthritis and that exacerbates arthritis when delivered by gene transfer. The current study was designed to determine the mechanism by which FSTL-1 promotes arthritis. FSTL-1 was injected into mouse paws, resulting in severe paw swelling associated with up-regulation of IFN-γ transcript and the IFN-γ-induced chemokine, CXCL10. Mice depleted of T cells were protected. A central role for IFN-γ was confirmed by the finding that mice deficient in IFN-γ failed to exhibit paw swelling in response to injection of FSTL-1. Furthermore, IFN-γ secretion from mouse spleen cells exposed to a weak TCR signal was increased 5-fold in the presence of FSTL-1. FSTL-1 could be induced by innate immune signals, including TLR4 agonists and the arthritogenic cytokine, IL-1β, via an NFκB pathway. Finally, FSTL-1 was found to be overexpressed in human arthritis and its neutralization inhibited murine collagen-induced arthritis and suppressed IFN-γ and CXCL10 production in arthritic joints. These findings demonstrate that FSTL-1 plays a critical role in arthritis by enhancing IFN-γ signaling pathways and suggest a mechanism by which FSTL-1 bridges innate and adaptive immune responses.

Efficacy and complications of adalimumab treatment for medically-refractory Crohn's disease : analysis of nationwide experience in Scotland (2004-2008)

Background  Adalimumab is a second generation humanized anti‐tumour necrosis factor (TNF) monoclonal antibody with established efficacy in Crohn’s disease (CD).

Follistatin-like protein 1 is a mesenchyme-derived inflammatory protein and may represent a biomarker for systemic-onset juvenile rheumatoid arthritis

OBJECTIVE To examine both the source of follistatin-like protein 1 (FSTL-1) and the factors that induce its expression in arthritis, and to determine whether juvenile rheumatoid arthritis (JRA) is characterized by overexpression of FSTL-1. METHODS FSTL-1 expression patterns were analyzed by immunohistochemical staining of joint tissue derived from mice with collagen-induced arthritis. Induction of FSTL-1 secretion was assessed in osteoblasts, adipocytes, and human fibroblast-like synoviocytes in response to transforming growth factor beta (TGFbeta), interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and IL-6. In addition, sera and synovial fluid from children with oligoarticular, polyarticular, or systemic-onset JRA were assayed for FSTL-1 using a custom enzyme-linked immunosorbent assay. FSTL-1 concentrations in these patients were assessed for correlations with the erythrocyte sedimentation rate (ESR) and platelet count. RESULTS Immunohistochemical staining of murine joint sections demonstrated expression of FSTL-1 in all cell types of the mesenchymal lineage, including osteocytes, chondrocytes, adipocytes, and fibroblasts. FSTL-1 could be induced in osteoblasts, adipocytes, and human fibroblast-like synoviocytes by TGFbeta, IL-1beta, TNFalpha, and IL-6. The IL-1beta response was significantly greater than the TNFalpha response (P < 0.05). In human serum and synovial fluid, only those samples from children with the systemic-onset JRA subtype had elevated concentrations of FSTL-1. The synovial fluid concentrations of FSTL-1 were 2-3-fold higher than the serum concentrations. The elevation in serum FSTL-1 concentrations seen in children with systemic-onset JRA correlated closely with elevations in the ESR and platelet count. CONCLUSION These findings demonstrate that the arthritic joint matrix is a major source of FSTL-1 and that IL-1beta is a central mediator of FSTL-1 secretion. Furthermore, FSTL-1 may represent a useful biomarker of disease activity in systemic-onset JRA.

Akt Fine-tunes NF-κB-dependent Gene Expression during T Cell Activation

Background: The precise role of the Akt kinase in NF-κB induction by the TCR and CD28 is still unclear. Results: We have found that Akt makes a quantitative contribution to NF-κB induction in T cells, selectively impacting a subset of downstream genes. Conclusion: Although Akt is not a canonical member of the NF-κB pathway, it can modulate NF-κB signaling and transcription. Significance: These findings may open the way to more selective modulation of NF-κB-dependent pathways. Activation of the NF-κB signaling pathway is critical for leukocyte activation and development. Although previous studies suggested a role for the Akt kinase in coupling the T cell antigen receptor and CD28 to NF-κB activation in T cells, the nature of the role of Akt in this pathway is still unclear. Using a targeted gene profiling approach, we found that a subset of NF-κB-dependent genes required Akt for optimal up-regulation during T cell activation. The selective effects of Akt were manifest at the level of mRNA transcription and p65/RelA binding to upstream promoters and appear to be due to altered formation of the Carma1-Bcl10 complex. The proinflammatory cytokine TNF-α was found to be particularly sensitive to Akt inhibition or knockdown, including in primary human blood T cells and a murine model of rheumatoid arthritis. Our findings are consistent with a hierarchy in the expression of NF-κB-dependent genes, controlled by the strength and/or duration of NF-κB signaling. More broadly, our results suggest that defining the more graded effects of signaling, such as those demonstrated here for Akt and the NF-κB pathway, is important to understanding how cells can fine-tune signaling responses for optimal sensitivity and specificity.

Plasma Follistatin-Like Protein 1 is Elevated in Kawasaki Disease and May Predict Coronary Artery Aneurysm Formation

OBJECTIVE To determine whether plasma levels of follistatin-like protein 1 (FSTL-1), a pro-inflammatory protein produced by mesenchymal tissue, including cardiac myocytes, correlate with the development of Kawasaki disease (KD) and coronary artery aneurysms (CAA). STUDY DESIGN FSTL-1 plasma levels were measured serially with enzyme-linked immunosorbent assay in 48 patients with KD at time of diagnosis and, when available, 2 weeks, 6 weeks, and 6 months after onset of disease. These were compared with FSTL-1 plasma levels in 23 control subjects. Data were analyzed with generalized estimating equations. RESULTS Plasma FSTL-1 levels were elevated in patients with acute KD compared with control subjects (P = .0086). FSTL-1 levels remained significantly elevated at 2 weeks after disease onset, but returned to control levels by 6 months. Seven patients with CAA had significantly higher FSTL-1 levels at the time of diagnosis than patients in whom aneurysms did not develop (P = .0018). Sensitivity and specificity rates for CAA at a specific FSTL-1 cutoff point (178 ng/mL) were 85% and 71%. CONCLUSIONS Plasma levels of FSTL-1 are elevated in acute KD and may predict cardiac morbidity in this disease. These results suggest a possible role for FSTL-1 in the formation of CAAs.

What's Hot in the Red Journal This Month?

This retrospective study aimed to review the evaluation and management of autoimmune pancreatitis (AIP) in 26 patients seen at a large tertiary center from 1998 to 2007. The most common presentation included new-onset mild abdominal pain (65%), jaundice (62%), and weight loss (42%). Pancreatic mass, enlargement, or prominence on imaging was present in 85% of patients. When measured, serum IgG4 was elevated in 44% at presentation. The most common extrapancreatic finding was biliary strictures (35%). Peripancreatic vascular complications were noted in 23%. Six patients underwent partial or complete pancreatectomy. Partial or complete response to initial steroid treatment was seen in 19 patients and to methotrexate in 1 patient. Recurrences were common, especially in patients with extrapancreatic manifestations, and usually responded to a combination of steroids and azathioprine. Any one of the commonly used diagnostic criteria was fulfilled in 85% of cases. This major US series confirms several findings previously reported in AIP and highlights the presence of vascular complications in a subset of AIP patients. The current diagnostic criteria may not identify all AIP patients. See page 2295 and Editorial, page 2307

Mo1989 Serum D-Lactate: A Novel Biomarker for Severe Small Bowel Bacterial Overgrowth in Children With Intestinal Failure

was to evaluate the clinical outcomes, particularly with regards to IBD, in children presenting with abdominal pain who have findings of thickened bowel wall on CT scan. METHODS: A retrospective analysis of pediatric patients at two large military medical centers with CT findings of thickened bowel wall was performed between January 2007 and April 2011. Patients with no known underlying disease, presenting with abdominal pain in the outpatient setting were included. Endoscopic findings and their clinical variables, as well as follow up assessments in those who did not undergo endoscopy, were evaluated. RESULTS: 56 patients (mean age 13.7 years) presenting with abdominal pain in the outpatient setting who had thickened bowel wall findings on CT scan were identified. 27% had isolated TI thickening, 23% had both TI and colonic thickening, while 29% had colonic involvement only. Of the 56 patients, 20 (36%) underwent endoscopic evaluation. 11 of those 20 (55%) were ultimately diagnosed with IBD based on histology and their clinical picture. The lab variables that most strongly predicted IBD in these patients included ESR>22 (100% had IBD), CRP>1.5 (100%), albumin 320 (82%), and hemoglobin (hgb)<12 (62%). Of the remaining patients who did not undergo endoscopy, 25% had appendicitis, 27% had infectious gastroenteritis and 22% were diagnosed with functional pain. Additional follow up of these patients for an average of 22 months beyond the original CT scan revealed no new diagnoses of IBD. CONCLUSIONS: The presence of thickened bowel wall on CT scans is a non-specific finding in children. Ultimately, 20% of our patients were diagnosed with IBD, suggesting that urgent subspecialty evaluation may not always be warranted. However, laboratory screening with ESR, CRP, albumin, platelets, and hgb, utilizing the cutoff values described, would have accurately separated most of our patients with IBD. The use of these screening tests on patients noted to have bowel wall thickening may help distinguish which patients require additional evaluation and endoscopy.

Mo1981 The Utility of a Faecal Calprotectin Cut off of >200ug/G in a Regional Paediatric Population

Background: A poor dietary habit, particularly inadequate vegetable consumption, is often cited as a contributing factor toward the development of digestive complaints in children. This is a pilot study to assess childrens familiarity with vegetables in an ambulatory pediatric gastroenterology practice. Methods: 76 consecutive patients between the ages of 8 and 18 years who presented for pediatric gastroenterology office visits over a 5 week period were prospectively asked during the visits to name as many different varieties of vegetables as possible in 30 seconds. Each patients age, gender, BMI, BMI-for-age percentile, primary diagnosis, list of vegetables named in order, and the number of vegetables named, were recorded. Microsoft Excel was used for data analysis. Results: The average number of vegetables named in 30 seconds was approximately 6. There was a trend toward gradual improvement with age, from an average of 3.9 +/0.4 (S.E.M.) in the 8-10 year old group to 6.9 +/0.5 in the 16-18 year group. Results were similar across gender and BMI-for-age percentile categories. 38 distinct vegetables were named; however, only carrot (85.5%), broccoli (75.0%), tomato (63.2%) and lettuce (50.0%) were named by at least half of the patients, and 21 of the vegetables were named less than 10% of the time. Several patients answered “pickles” as a vegetable choice, but did not know that pickles are made from cucumbers. Conclusion: Familiarity with vegetables appears to be poor among most youths who present for pediatric gastroenterology visits, regardless of gender or BMI-for-age percentiles.

Long term follow-up of Children with 6-Thioguanine related Chronic Hepatoxicity following Treatment for Acute Lymphoblastic Leukemia

6-Thioguanine (6-TG) therapy in childhood acute lymphoblastic leukaemia results in chronic hepatotoxicity and portal hypertension. We report follow-up data in a cohort of 10 children with acute lymphoblastic leukaemia and 6-TG-related hepatotoxicity described initially in 2006. Clinically significant portal hypertension was present in the majority of patients several years after cessation of 6-TG treatment. These data reflect the natural history of noncirrhotic portal hypertension and emphasises the need to incorporate ongoing surveillance in the transition arrangement to adult services in this select group of patients.