Background: IL-36 proteins are IL-1 family members with a key role in the skin. Results: Truncation of IL-36 ligands and IL-36Ra is required for full activity. IL-36Ra binds IL-1Rrp2 and prevents signaling. Conclusion:The mechanism of action of IL-36Ra is directly analogous to that of IL-1Ra. Significance: Protease(s) that activate IL-36 cytokines could be excellent drug targets for psoriasis.

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SUMMARY IL-1 has multiple functions in both the periphery and the central nervous system (CNS) and is regulated at many levels. We identified a novel isoform of the IL-1R Accessory Protein (termed AcPb) that is expressed exclusively in the CNS. AcPb interacted with IL-1 and the IL-1 receptor but was unable to mediate canonical IL-1 responses. AcPb expression, however, modulated neuronal gene expression in response to IL-1 treatment in vitro. Animals lacking AcPb demonstrated an intact peripheral IL-1 response and developed experimental autoimmune encephalomyelitis (EAE) similarly to wild type mice. AcPb-deficient mice were instead more vulnerable to local inflammatory challenge in the CNS and suffered enhanced neuronal degeneration as compared to AcP-deficient or wild type mice. These findings implicate AcPb as an additional component of the highly regulated IL-1 system and suggest it may play a role in modulating CNS responses to IL-1 and the interplay between inflammation and neuronal survival.

We have identified a novel cytoplasmic protein, leupaxin, that is preferentially expressed in hematopoietic cells and is most homologous to the focal adhesion protein, paxillin. Leupaxin possesses two types of protein interaction domains. There are four carboxyl-terminal LIM domains in leupaxin that share 70% amino acid identity and 80% similarity with those in paxillin. Paxillin LIM domains mediate localization to focal contacts. In the amino-terminal region of leupaxin there are three short stretches of approximately 13 amino acids that share 70 -90% similarity with paxillin LD motifs. Paxillin LD motifs have been implicated in focal adhesion kinase (FAK) and vinculin binding resulting in the localization of FAK to focal adhesions. Leupaxin is expressed in cell types, such as macrophage, that lack FAK. We demonstrate here that leupaxin associates with a second FAK family member, PYK2. As leupaxin and PYK2 are both preferentially expressed in leukocytes they may therefore form a cell type-specific signaling complex. We also demonstrate that leupaxin is a substrate for a tyrosine kinase in lymphoid cells and thus may function in and be regulated by tyrosine kinase activity. Leupaxin is thus a phosphotyrosine protein with LD and LIM binding motifs most homologous to paxillin that may assemble and regulate PYK2 signaling complexes in leukocytes.Cell adhesion, spreading, and migration are mediated by integrin interactions with extracellular and cell surface ligands (1, 2). In adherent cell types such as epithelial cells and fibroblasts a complex of cytoplasmic proteins localizes to the termini of actin bundles at sites of integrin-dependent close cell contact with substratum or extracellular matrix proteins (3). These complexes, designated focal adhesions, have been implicated in the regulation of cell locomotion, survival, and proliferation (4, 5).Focal adhesions are rich in tyrosine kinases and tyrosinephosphorylated proteins, which may reflect a role for tyrosine kinases in integrin signaling (6, 7). Protein-tyrosine kinases that are focal adhesion proteins includes focal adhesion kinase (FAK), 1 Src, and Src family kinases. A second FAK family member, PYK2, has been identified by several groups and designated CAK␤ (8), RAFTK (9), FAK2 (10), and CADTK (11). PYK2 and FAK are closely related in their overall structure, and both are phosphorylated on tyrosine in response to integrin engagement, T cell receptor engagement or chemokine stimulation (12-15). These stimuli all modulate integrin-dependent adhesion. PYK2 and FAK both associate with paxillin, p130cas , and Src (16,17). Although PYK2 possesses a focal adhesion targeting domain that is highly homologous with FAK, the majority of PYK2 displays a more diffuse cytoplasmic distribution with a small percent present in focal adhesions (18). This indicates that FAK and PYK2 may possess both overlapping and unique functions.Tyrosine phosphoproteins present in focal adhesions include FAK, vinculin, zyxin, and paxillin. A second paxillin family member, Hic-5, has rece...

CD11c, a member of the leukointegrin family, is expressed prominently on tissue macrophages and dendritic cells and binds to complement fragment (iC3b), provisional matrix molecules (fibrinogen), and the Ig superfamily cell adhesion molecule, ICAM-1. CD11c has been proposed to function in phagocytosis, cell migration, and cytokine production by monocytes/macrophages as well as induction of T cell proliferation by Langerhans cells. Using assays to quantify CD11c-mediated cell adhesion, we demonstrate that CD11c recognizes ICAM-2 and VCAM-1. The CD11c-binding site on VCAM-1 appears to be different from that used by the integrin alpha4. CD11c and alpha4beta1 contributed to monocyte capture and transmigration on inflamed human aortic endothelial cells. We discovered that the anti-mouse CD11c mAb N418 blocks CD11c binding to iC3b, ICAM-1, and VCAM-1. Treatment of mice with N418 reduced SRBC-induced delayed-type hypersensitivity significantly. CD11c appeared to contribute predominantly to the sensitization phase and somewhat less to the response to SRBC challenge. This suggests a novel role for CD11c during leukocyte recruitment, antigen uptake, and the survival of APC.