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After infection with Borrelia burgdorferi, humans and mice under certain conditions develop arthritis. Initiation of inflammation is dependent on the migration of innate immune cells to the site of infection, controlled by interactions of a variety of adhesion molecules. In this study, we used the newly synthesized compound S18407, which is a prodrug of the active drug S16197, to analyze the functional importance of α4β1-dependent cell adhesion for the development of arthritis and for the antibacterial immune response. S16197 is shown to interfere specifically with the binding of α4β1 integrin to its ligands VCAM-1 and fibronectin in vitro. Treatment of B. burgdorferi-infected C3H/HeJ mice with the α4β1 antagonist significantly ameliorated the outcome of clinical arthritis and the influx of neutrophilic granulocytes into ankle joints. Furthermore, local mRNA up-regulation of the proinflammatory mediators IL-1, IL-6, and cyclooxygenase-2 was largely abolished. Neither the synthesis of spirochete-specific Igs nor the development of a Th1-dominated immune response was altered by the treatment. Importantly, the drug also did not interfere with Ab-mediated control of spirochete load in the tissues. These findings demonstrate that the pathogenesis, but not the protective immune response, in Lyme arthritis is dependent on the α4β1-mediated influx of inflammatory cells. The onset of inflammation can be successfully targeted by treatment with S18407.

Aromatic b-amino acid esters 2a-h were prepared in racemic and enantiomerically pure form by the Radionow reaction or based on the method described by Davis and used as mimics of the Asp-Phg C-terminus in LDV derived VLA-4 antagonists. As a promising b-amino acid ester, 11 was identified and used for the synthesis of the highly potent VLA-4 antagonist S9059 with an IC 50 of 1.6 nM in a cell attachment assay.

The common gamma-chain (␥c) is a component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 and is essential for their signal transduction. Western blotting and a newly established enzyme-linked immunosorbent assay detected substantial constitutive levels (50-250 ng/mL) of soluble ␥c (s␥c) in sera of murine inbred strains. It was demonstrated that purified immune cells, such as T, B, and natural killer cells, and macrophages released this protein after activation. Transfection experiments with cDNA encoding the fulllength ␥c showed that shedding of the transmembrane receptor led to the release of s␥c. The shedding enzymes, however, appeared to be distinct from those cleaving other cytokine receptors because inhibitors of metalloproteases (eg, TAPI) did not influence s␥c release. In vivo, superantigen-induced stimulation of T cells enhanced s␥c serum concentrations up to 10-fold within 6 hours. Because these findings demonstrated regulated expression of a yet unknown molecule in the immune response, further experiments were performed to assess the possible function(s) of s␥c. A physiological role of s␥c was indicated by its capacity to specifically inhibit cell growth induced by ␥c-dependent cytokines. Mutational analysis revealed that the Cterminus and the WSKWS motif are essential for the cytokine inhibitory effect of the s␥c and for binding of the molecule to cytokine receptor-expressing cells. Thus, competitive displacement of the transmembrane ␥c by excess s␥c is the most likely mechanism of cell growth inhibition. It was implied that naturally produced s␥c is a negative modulator of ␥c-dependent cytokines. IntroductionThe murine common gamma-chain (␥c) is a 64-kd type 1 transmembrane protein of the cytokine receptor family. 1 Although the ␥c alone is unable to bind to cytokines, it has been shown to be an essential component of the cell surface receptor complexes of IL-2, IL-4, IL-7, IL-9, and IL-15. 1 Interaction of the respective cytokines with the ␥c within the receptor complexes results in the activation of the Janus kinase JAK3, 2 which subsequently interacts with Pyk2, a member of focal adhesion tyrosine kinases, leading to the phosphorylation of this protein. 3 Recent studies have shown that the ␥c is critical for lymphoid development because genetic defects of either this molecule 4 or JAK3 5 in humans or targeted deletions of the ␥c 6,7 or JAK3 8-10 in mice severely impair the development of T and B cells, leading to severe combined immune deficiency syndromes (SCID). 11 Soluble cytokine receptors and growth factor receptors are present as immunomodulatory molecules in body fluids of humans and mice (reviewed in references 12 and 14). Two major nonexclusive mechanisms are responsible for the generation of soluble cytokine receptors: proteolytic cleavage of transmembrane receptors catalyzed mostly by metalloproteases [15][16][17][18][19] or de novo synthesis of alternatively spliced mRNAs encoding soluble receptor molecules lacking a transmembrane domain. [20][21][22][23][24][25][26][27][28] ...