Cytokines are important in the regulation of haematopoiesis and immune responses, and can influence lymphocyte development. Here we have identified a class I cytokine receptor that is selectively expressed in lymphoid tissues and is capable of signal transduction. The full-length receptor was expressed in BaF3 cells, which created a functional assay for ligand detection and cloning. Conditioned media from activated human CD3+ T cells supported proliferation of the assay cell line. We constructed a complementary DNA expression library from activated human CD3+ T cells, and identified a cytokine with a four-helix-bundle structure using functional cloning. This cytokine is most closely related to IL2 and IL15, and has been designated IL21 with the receptor designated IL21 R. In vitro assays suggest that IL21 has a role in the proliferation and maturation of natural killer (NK) cell populations from bone marrow, in the proliferation of mature B-cell populations co-stimulated with anti-CD40, and in the proliferation of T cells co-stimulated with anti-CD3.

A structural, profile-based algorithm was used to identify interleukin 20 (IL-20), a novel IL-10 homolog. Chromosomal localization of IL-20 led to the discovery of an IL-10 family cytokine cluster. Overexpression of IL-20 in transgenic (TG) mice causes neonatal lethality with skin abnormalities including aberrant epidermal differentiation. Recombinant IL-20 protein stimulates a signal transduction pathway through STAT3 in a keratinocyte cell line, demonstrating a direct action of this ligand. An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis.

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BackgroundTumor progression locus 2 (TPL2, also known as MAP3K8) is a mitogen-activated protein kinase kinase kinase and the primary regulator of ERK-mediated gene transcription downstream of multiple proinflammatory stimuli including bacterial products (eg, LPS and bacterial peptidoglycans), damage-associated molecular patterns (DAMPs), TNFα, and IL-1β.1 Dysregulated signaling downstream of these inflammatory signals can drive uncontrolled immune cell activation and inflammation, which is associated with multiple chronic inflammatory and autoimmune diseases. As such, TPL2 inhibition represents a strategy to modulate inflammation in a variety of disease settings.ObjectivesWe evaluated the effect of a highly selective TPL2 inhibitor on inflammatory signaling and cytokine production in LPS and TNFα-stimulated primary human monocytes.MethodsMonocytes were precultured with a TPL2 inhibitor and stimulated with LPS or TNFα, and phosphosignaling and cytokine production were then evaluated at 30 minutes and 4 hours poststimulation. A431 cells (human epidermoid carcinoma cell line) were stimulated with TNFα or EGF and phospho–ERK was evaluated after 30 minutes.ResultsTPL2 inhibition selectively inhibited LPS and TNFα-stimulated phosphorylation of TPL2, MEK, and ERK, with little to no inhibition of phosphorylated p38, JNK, or p65 observed. TPL2 inhibition similarly inhibited both the RNA production and secretion of TNFα, IL-1β, IL-6, and IL-8 following LPS stimulation in primary human monocytes. To confirm TPL2 requirement for inflammatory, but not Ras-mediated (growth factor stimulated) ERK signaling, A431 cells were stimulated with either TNFα or EGF. Although TPL2 inhibition reduced TNFα-stimulated pERK, no effect on ERK activation downstream of EGF was observed.ConclusionThis work demonstrates the selective effects of TPL2 inhibition on ERK-mediated signaling and proinflammatory cytokine gene transcription in primary human monocytes and highlights the potential for TPL2 inhibition to treat diseases associated with dysregulated inflammatory signaling and chronic inflammation.Reference[1] Gantke T, Sriskantharajah S, Ley S. Cell Res. 2011;21:131-145.Disclosure of InterestsMatthew R. Warr Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Angie Hammond Grant/research support from: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Grace Park Grant/research support from: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Nathan Wright Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., James Taylor Grant/research support from: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc.