Interleukin-1 and Cutaneous Inflammation: A Crucial Link Between Innate and Acquired Immunity  Jo-Ellen Murphy, Caroline Robert, Thomas S. Kupper  Journal of Investigative Dermatology  Volume 114, Issue 3, Pages 602-608 (March 2000) DOI: 10.1046/j.1523-1747.2000.00917.x Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 IL-1 induces the transcription of genes involved in skin inflammation via activation of the transcription factor NF-κB. The membrane bound IL-1R type 1 can bind either IL-1α or IL-1β and, when complexed to the receptor accessory protein, will initiate the signal transduction cascade that ultimately results in stimulation of transcription of adhesion molecules, cytokines, and pro-inflammatory genes. This complex recruits the adaptor molecule MyD88 that binds to the IRAKs. The IRAKs bind to another adaptor molecule, TNF receptor associated factor 6, which associates with TAK1, the kinase that phosphorylates the NF-κB-inducing kinase. NF-κB-inducing kinase activates the IKK, which can phosphorylate IκB, causing its rapid degradation. NF-κB is then free to migrate into the nucleus, where it binds to specific sequences (κB sites) in the promoter region of multiple inflammatory genes. Journal of Investigative Dermatology 2000 114, 602-608DOI: (10.1046/j.1523-1747.2000.00917.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 The signaling pathway for the innate immune response is highly conserved through evolution. Components of the signaling cascade for mammalian, insect, and plant innate immunity possess striking homology, from cell surface receptors to transcriptional activators that localize to the nucleus following ligand binding. In mammals, receptors for IL-1, IL-18, and lipopolysaccharide, and in Drosophila for späetzle, all share an intracellular IL-1R1-like domain called a TIR domain (filled box). Several plant proteins utilized for pathogen resistance and defense also have TIR domains: the tobacco N-gene product (a cytoplasmic protein), the flax L6 and M proteins, and Arapidopsis Rpp5. The similarities also extend to the downstream components of the pathways, including the intracellular adaptors and kinases. The species diversity is reflected in the extracellular domains of the membrane-bound receptors: the Drosophila receptors Toll and 18-wheeler and the mammalian Tlrs have regions of leucine-rich repeats (striped box). In contrast, the extracellular domains of the IL-1 family members, IL-1R1 and IL-18R, have immunoglobulin-like sequences. The function and associations of each of the components are described in the text. Journal of Investigative Dermatology 2000 114, 602-608DOI: (10.1046/j.1523-1747.2000.00917.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Skin injury leads to cutaneous inflammation and to recruitment of CLA+ T cells. Primary cytokines and microbial products activate the NK-κB pathway and upregulate the expression of adhesion molecules (E- and P-selectins, ICAM-1, and VCAM-1) and chemokines on skin endothelial cells. CLA+ T cells can tether and roll on skin endothelium via the binding of the PSGL-1/CLA molecules on endothelial E- and P-selectins. Rolling lymphocytes can then be activated by inflammatory chemokines displayed on the surface of endothelial cells. Upon activation, they attach firmly to the endothelium through binding of their surface integrins, LFA-1 and VLA-4 to ICAM-1 and VCAM-1, respectively. This multistep pathway: tethering and rolling on selectin-selectin ligands, activation by chemokine via chemokine receptors, and firm adhesion via integrin-binding to endothelial CAMs, can eventually lead to extravasation of the CLA+ T cell into skin. If the extravasated CLA+ T cell recognizes the antigen for which it is specific in the cutaneous environment, it will be activated to produce T cell cytokines that further modify and amplify the immune response. Journal of Investigative Dermatology 2000 114, 602-608DOI: (10.1046/j.1523-1747.2000.00917.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions