Tumor necrosis factor psoriasis

Etanercept is a fully human dimeric fusion protein composed of human TNF-a p75 receptor fused to the Fc portion of human IgG 1.41 It acts as a tumor necrosis factor-a (TNF-a) inhibitor by binding to and inactivating TNF-a, thus preventing interactions with its cell surface receptors.41 This agent is useful for chronic moderate to severe plaque psoriasis and for psoriatic... 

Once T cells are activated, they migrate from lymph nodes and the bloodstream into skin and secrete various cytokines (e.g., interferon % interleukin 2 [IL-2]) that induce the pathologic changes of psoriasis. Local keratinocytes and neutrophils are induced to produce other cytokines, such as tumor necrosis factor-a (TNF-a), IL-8, and others. 

Etanercept is a recombinant human soluble tumor necrosis factor-alpha (TNFo ) receptor fusion protein that binds to TNFo and decreases its role in disorders involving excess inflammation. It is approved for subcutaneous use in the treatment of patients with moderate to severe active rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing arthritis and plaque psoriasis. To the adverse reactions mentioned for infliximab, rare reports of congestive heart failure should be added. 

Weinberg JM et al Biologic therapy for psoriasis An update on the tumor necrosis factor inhibitors infliximab, etanercept, and adalimumab, and the T-cell-targeted therapies efalizumab and alefacept. J Drugs Dermatol 2005 4 544. [PMID 16167412]... 

Krueger, G. and K. Callis, Potential of tumor necrosis factor inhibitors in psoriasis and psoriatic arthritis. Arch. Dermatol., 2004, 140 218-25. 

Victor, F.C., Gottlieb, A.B., and Menter, A. 2003. Changing paradigms in dermatology Tumor necrosis factor alpha (TNF-alpha) blockade in psoriasis and psoriatic arthritis. Clin Dermatol 21 392-397. 

The cytokine profile in psoriasis is known as a T-helper cell type 1 (Thl) response this subset of T cells produces primarily interferon-y (IFN-y) and interleukin (IL)-2. Other local cells, including keratinocytes and local neutrophils, are induced to produce other cytokines, including tumor necrosis factor-a (TNF-a) and interleukin... 

Boyman, O., Hefti, H.P., Conrad, C., Nicko-loff, B.J., Suter, M., and Nestle, F.O. (2004) Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha, J Exp Med 199, 731-736. 

Etanercept (Enbrel) is FDA approved for the treatment of psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, and ankylosing spondylitis. Etanercept is a soluble, recombinant, fully human tumor necrosis factor (TNF) receptor fusion protein consisting of two molecules of the hgand-binding portion of the TNF receptor fused to the Fc portion of IgGl. As a dimeric molecule, it can bind two molecules of TNF. Etanercept binds soluble and membrane-bound TNF, thereby inhibiting the action of TNF. 

Wollina U, Hansel G, Koch A, Schonlebe J, Kostler E, Haroske G. Tumor necrosis factor-alpha inhibitor-induced psoriasis or psoriasiform exanthemata first 120 cases from the literature including a series of six new patients. Am J Clin Dermatol 2008 9(1) 1-14. 

Mossner R, Schon MP, Reich K. Tumor necrosis factor antagonists in the therapy of psoriasis. Qin Dermatol 2008 26(5) 486-502. 

MAPKAP-K2 (MK-2), a direct substrate of p38 MAPKs, has been shown to play an important role in the production of pro-inflammatory cytokines, such as tumor necrosis factor-a (TNF-a), interleukin-1 a (IL-la) and IL-6. Thus inhibition of MK-2 kinase activity may potentially be useful for treatment of inflammatory diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel disease. Two classes of MK-2 inhibitors based on carboline or pyrazinoindolone templates are highlighted. Extensive SAR efforts lead to compounds with single-digit nanomolar molecular potency. Further optimization of pyrazinoindolone-based inhibitors provides compounds with the sub-micromolar cellular potency. 

Tumor necrosis factor alpha (TNFa) and interleukin-1 beta (IL-1(3) are proinflammatory cytokines implicated in many inflammatory diseases such as rheumatoid arthritis (RA), inflammatory bowel disease, and psoriasis. P38a is a mitogen activated protein (MAP) kinase that plays an essential role in the signal transduction pathways leading to the synthesis of TNFa and IL-1(3. Thus, inhibition of p38 MAP kinase has remained a popular drug development target for orally active small molecules. 

Nickoloff BJ, Karabin GD, Barker JWCN, et al. Cellular localization of interleukin-8 and its inducer, tumor necrosis factor-alpha in psoriasis. Am J Pathol 1991 ... 

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