transforming-growth-factor-beta and Rheumatic-Diseases

Pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α are central regulators of autoinflammatory diseases. While targeting these cytokines has proven to be a successful clinical strategy, the long-term challenges such as drug resistance, lack of efficacy and poor clinical outcomes in some patients are some of the limitations faced by these therapies. This has ignited strategies to reduce inflammation by potentially targeting a variety of molecules, including cell surface receptors, signalling proteins and/or transcription factors to minimize cytokine-induced inflammation and tissue injury. In this regard, transforming growth factor β activated kinase 1 (TAK1) is activated in the inflammatory signal transduction pathways in response to IL-1β, TNF-α or toll-like receptor stimulation. Because of its ideal position upstream of mitogen-activated protein kinases and the IκB kinase complex in signalling cascades, targeting TAK1 may be an attractive strategy for treating diseases characterized by chronic inflammation. Here, we discuss the emerging role of TAK1 in mediating the IL-1β, TNF-α and toll-like receptor mediated inflammatory responses in diseases such as RA, OA, gout and SS. We also review evidence suggesting that TAK1 inhibition may have potential therapeutic value. Finally, we focus on the current status of the development of TAK1 inhibitors and suggest further opportunities for testing TAK1 inhibitors in rheumatic diseases.

Topics: Antirheumatic Agents; Cytokines; Female; Humans; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Male; MAP Kinase Kinase Kinases; Molecular Targeted Therapy; Prognosis; Rheumatic Diseases; Transforming Growth Factor beta

Systemic sclerosis (SSc) is a generalized connective tissue disorder, characterized by a wide spectrum of microvascular and immunological abnormalities, leading to a progressive thickening and fibrosis of the skin and other organs, such as the lungs, GI tract, heart and kidneys. SSc is thought to be an autoimmune disease owing to the presence of high affinity antibodies and possible clinical overlap with other autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Autoimmune diseases arise because of a breakdown in immunological self tolerance. Self tolerance is maintained via multiple regulatory mechanisms within the immune system, including the thymic deletion of self-reactive T cells and mechanisms of peripheral tolerance. In recent years, the presence of CD4(+)CD25(+)FOXP3(+) Tregs has been identified as a major mechanism of peripheral tolerance, and accumulating evidence indicates that alterations in Treg frequencies and/or function may contribute to autoimmune diseases. Here, we will review recent data on the percentage, function and phenotype of CD4(+)CD25(+) Tregs in rheumatic disease, and discuss how recent developments may guide research in this area in SSc.

Topics: Animals; Autoantibodies; CD4 Antigens; Cell Communication; Fibrosis; Forkhead Transcription Factors; Humans; Interleukin-2 Receptor alpha Subunit; Rheumatic Diseases; Scleroderma, Systemic; Self Tolerance; Skin; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

As you saw in the first part of this description of interleukins, normal orchestration of wound healing, the protective immune response and inflammation involves many cells that must effectively communicate with each other. The means of this communication is often soluble messengers (cytokine) and many of them bear the title interleukin. Although all these messengers have a role in normal immune homeostasis, it is apparent that many are involved in tissue damage in a variety of disease, eg, rheumatoid arthritis, osteoarthritis. I dealt with interleukins (IL) 3 to 16 in the first part of this project. We now pick up the story with IL-17. Turns out, much of the most exciting recent work in rheumatology has focused on IL-17 and IL-18. The disparate effects of the interleukins may be confusing, often a single cytokine producing multiple effects seemingly at crossed purposes, but we are in our infancy when it comes to insights into the molecular biology of normal immune function, homeostasis, inflammation, and disease.

Topics: Humans; Interleukins; Rheumatic Diseases; Transforming Growth Factor beta

Pulmonary hypertension (PH) is a progressive disease of the pulmonary vasculature characterized by increased vascular resistance and pressure overload of the right ventricle. Histologically, PH lungs demonstrate medial hypertrophy of small pulmonary arteries and proliferation of endothelial cells resulting in plexiform lesions. Recent studies have identified mutations of the bone morphogenetic protein receptor 2 (BMPR2) gene and the activin-receptor-like kinase 1 (ALK1) gene, that affect the transforming growth factor beta (TGF-beta) receptor superfamily, a group of transmembrane signaling molecules with serine-threonine kinase activity that are involved in the regulation of cell growth. Several lines of evidence indicate that the development of PH is a multi-hit process, where one of the events is having a gene mutation and another might be a circumstantial condition or other disease-modifying genes. It is unknown which mechanism that is critical in rheumatic diseases causes pulmonary vascular disease. PH is most frequently associated with systemic sclerosis (SS), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD), however, it is still a rare manifestation of these disorders. For example, approximately 10% of SS cases manifest pulmonary vascular disease. In recent years symptomatic vasodilator therapies have been employed and have been able to improve exercise capacity and survival in these patients.

Topics: Activin Receptors, Type I; Activin Receptors, Type II; Anticoagulants; Bone Morphogenetic Protein Receptors, Type II; Cell Division; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Protein Serine-Threonine Kinases; Rheumatic Diseases; Signal Transduction; Transforming Growth Factor beta; Vascular Resistance; Vasodilator Agents