Differential expression of the FAK family kinases in rheumatoid arthritis and osteoarthritis synovial tissues

The focal adhesion kinase (FAK) family kinases, including FAK and proline-rich kinase 2 (Pyk)2, are the predominant mediators of integrin αvβ3 signaling events that play an important role in cell adhesion, osteoclast pathology, and angiogenesis, all processes important in rheumatoid arthritis (RA). Using immunohistochemical and western blot analysis, we studied the distribution of phospho (p)FAK, pPyk2, pSrc, pPaxillin and pPLCγ in the synovial tissue (ST) from patients with RA, osteoarthritis (OA) and normal donors (NDs) as well as in RA ST fibroblasts and peripheral blood differentiated macrophages (PB MΦs) treated with tumor necrosis factor-α (TNFα) or interleukin-1β (IL1β). RA and OA STs showed a greater percentage of pFAK on lining cells and MΦs compared with ND ST. RA ST fibroblasts expressed pFAK at baseline, which increased with TNFα or IL1β stimulation. Pyk2 and Src were phosphorylated more on RA versus OA and ND lining cells and MΦs. pPyk2 was expressed on RA ST fibrobasts but not in MΦs at baseline, however it was upregulated upon TNFα or IL1β activation in both cell types. pSrc was expressed in RA ST fibroblasts and MΦs at baseline and was further increased by TNFα or IL1β stimulation. pPaxillin and pPLCγ were upregulated in RA versus OA and ND lining cells and sublining MΦs. Activation of the FAK family signaling cascade on RA and OA lining cells may be responsible for cell adhesion and migration into the diseased STs. Therapies targeting this novel signaling pathway may be beneficial in RA

Interleukin-18 as an in vivo mediator of monocyte recruitment in rodent models of rheumatoid arthritis

Abstract Introduction The function of interleukin-18 (IL-18) was investigated in pertinent animal models of rodent rheumatoid arthritis (RA) to determine its proinflammatory and monocyte recruitment properties. Methods We used a modified Boyden chemotaxis system to examine monocyte recruitment to recombinant human (rhu) IL-18 in vitro. Monocyte recruitment to rhuIL-18 was then tested in vivo by using an RA synovial tissue (ST) severe combined immunodeficient (SCID) mouse chimera. We defined monocyte-specific signal-transduction pathways induced by rhuIL-18 with Western blotting analysis and linked this to in vitro monocyte chemotactic activity. Finally, the ability of IL-18 to induce a cytokine cascade during acute joint inflammatory responses was examined by inducing wild-type (Wt) and IL-18 gene-knockout mice with zymosan-induced arthritis (ZIA). Results We found that intragraft injected rhuIL-18 was a robust monocyte recruitment factor to both human ST and regional (inguinal) murine lymph node (LN) tissue. IL-18 gene-knockout mice also showed pronounced reductions in joint inflammation during ZIA compared with Wt mice. Many proinflammatory cytokines were reduced in IL-18 gene-knockout mouse joint homogenates during ZIA, including macrophage inflammatory protein-3α (MIP-3α/CCL20), vascular endothelial cell growth factor (VEGF), and IL-17. Signal-transduction experiments revealed that IL-18 signals through p38 and ERK½ in monocytes, and that IL-18-mediated in vitro monocyte chemotaxis can be significantly inhibited by disruption of this pathway. Conclusions Our data suggest that IL-18 may be produced in acute inflammatory responses and support the notion that IL-18 may serve a hierarchic position for initiating joint inflammatory responses.http://deepblue.lib.umich.edu/bitstream/2027.42/112330/1/13075_2010_Article_2890.pd

Thyroid hormone receptor expression in cardiovascular disease and pharmacology

The heart is a major target organ for thyroid hormone actions. Thyroid hormone exerts effects on the myocardium, which are mediated by specific nuclear receptors. The thyroid hormone receptors (TR) are members of the steroid hormone receptor superfamily. These receptors regulate gene expression by binding to the promotor region of target genes as monomers, homodimers or heterodimers depending on the thyroid hormone response element (TRE) and the presence or absence of thyroid hormone. Aims of the study: 1. To evaluate the organ specific expression of TR rnRNA and protein distribution in different human tissues in relation to the levels in the heart. 2. To investigate if TR rnRNA expression is affected in heart failure that is due to dilated cardiomyopathy (DCM) or chronic valvular disease (CVD). 3. To investigate if TR subtype rnRNA expression is affected by amiodarone treatment. 4. To clarify whether AT-1 cardiomyocytes express TR rnRNA and protein. 5. To determine if propranolol may affect TR subtype rnRNA expression in mouse myocardium as well as in AT-1 cardiomyocytes. Conclusions: 1. Specific patterns of TR [alpha]1, [alpha]2, ß1, and ß2 mRNA and protein in heart and other tissues suggest tissue-specific expression of TR subtypes. The TR mRNA and protein concentration were rather high in heart compared to the other tissues. There is also a correlation between the pattern of TR rnRNA and protein distribution in heart. 2. TR 8, and ß2 mRNA show increased expression in the failing canine heart with DCM or CVD. 3. In mouse heart, amiodarone downregulated the levels of TR [alpha]1 and ß mRNA dosedependently in comparison to the control. There were however no differences in the TR[alpha]2 and TR62 rnRNA levels. 4. The AT-1 cardiomyocyte, like the mouse heart, expresses ligand-binding TR protein and TR [alpha]1 [alpha]2, ß1 and ß2 mRNA, although in lower quantities. This suggests a highly differentiated state of the AT-1 cardiomyocyte. This cell line can thus be suitable for studies of cellular effects of T3 on cardiac cells. 5. Propranolol downregulated the levels of TR[alpha]1 and ß1 rnRNA in mouse heart and of TRß1 rnRNA in AT-1 cardiomyocytes in comparison to control

Impact of obesity on autoimmune arthritis and its cardiovascular complications

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COVID-19 infection in patients with sarcoidosis: susceptibility and clinical outcomes

PURPOSE OF REVIEW: Patients with sarcoidosis may be at higher risk of coronavirus disease-19 (COVID-19) as over 90% of the patients have pulmonary involvement and many are treated with immunosuppressive agents. This review will summarize the current literature regarding sarcoidosis and COVID-19, with a particular focus on susceptibility, clinical outcomes, management, and approach to vaccination. RECENT FINDINGS: Data about COVID-19 and sarcoidosis include a number of case series and reports, cohort studies, and registries. Literature is not conclusive whether patients with sarcoidosis have increased susceptibility to COVID-19. Patients with moderate to severe impaired pulmonary function may be at increased risk of adverse outcomes and mortality. Whether immunosuppressive medication increases risk of COVID-19 severity or affects vaccination response is not yet clear. Novel approaches, such as telemedicine and home monitoring programs, are promising to ensure continuity of care for patients with sarcoidosis during the COVID-19 pandemic. SUMMARY: Current evidence about the risk and clinical outcomes of COVID-19 infection in patient with sarcoidosis, is mainly extrapolated from other immune-mediated diseases. Hence, further research that focuses on the sarcoidosis population is warranted