In this study, the cytokine-producing profile of progenitor T cells (pro-T cells) was determined. During screening of a complementary DNA library generated from activated mouse pro-T cells, a cytokine designated lymphotactin was discovered. Lymphotactin is similar to members of both the Cys-Cys and Cys-X-Cys chemokine families but lacks two of the four cysteine residues that are characteristic of the chemokines. Lymphotactin is also expressed in activated CD8+ T cells and CD4-CD8- T cell receptor alpha beta + thymocytes. It has chemotactic activity for lymphocytes but not for monocytes or neutrophils. The gene encoding lymphotactin maps to chromosome one. Taken together, these observations suggest that lymphotactin represents a novel addition to the chemokine superfamily.

The FLT3/FLK2 receptor tyrosine kinase is closely related to two receptors, c-Kit and c-Fms, which function with their respective ligands, Kit ligand and macrophage colony-stimulating factor to control differentiation of haematopoietic and non-haematopoietic cells. FLT3/FLK2 is thought to be present on haematopoietic stem cells and found in brain, placenta and testis. We have purified to homogeneity and partially sequenced a soluble form of the FLT3/FLK2 ligand produced by mouse thymic stromal cells. We isolated several mouse and human complementary DNAs that encode polypeptides with identical N termini and different C termini. Some variants contain hydrophobic transmembrane segments, suggesting that processing may be required to release soluble ligand. The purified ligand enhances the response of mouse stem cells and a primitive human progenitor cell population to other growth factors such as interleukins IL-3 and IL-6 and to granulocyte-macrophage colony-stimulating factor, and also stimulates fetal thymocytes.

Following traumatic injury to the spinal cord, hematogenous inflammatory cells including neutrophils, monocytes, and lymphocytes infiltrate the lesion in a distinct temporal sequence. To examine potential mechanisms for their recruitment, we measured chemokine mRNAs in the contused rat spinal cord, using specific and sensitive reverse transcriptase polymerase chain reaction (RT-PCR) dot-blot hybridization assays. The neutrophil chemoattractant GRO-alpha was 30-fold higher than control values at 6 hr postinjury and decayed rapidly thereafter. LIX, a highly related alpha-chemokine, also was elevated early postinjury. Monocyte chemoattractant peptide (MCP)-1 and MCP-5 mRNAs, potent chemoattractants for monocytes, were significantly elevated at the lesion epicenter at 12 and 24 hr postinjury and declined thereafter. Interferon-gamma-inducible protein, 10 kDa (IP-10), chemoattractant towards activated T-lymphocytes, was significantly elevated at 6 and 12 hr postinjury. The dendritic cell chemoattractant MIP-3alpha also was increased, perhaps contributing to the development of T-cell autoreactivity to neural components after spinal cord injury (SCI) in rats. Other beta-chemokines, including MIP-1alpha and RANTES (regulated on expression normal T-cell expressed and secreted), were minimally affected by SCI. Expression of chemokines, therefore, directly precedes the influx of target neutrophils, monocytes, and T-cells into the spinal cord postinjury, as noted previously. Thus, selective chemokine expression may be integral to inflammatory processes within the injured spinal cord as a mechanism of recruitment for circulating leukocytes.

ADAMTS proteinases, belonging to the adamalysin subfamily of metalloproteinases, have been implicated in a variety of cellular events such as morphogenesis, cell migration, angiogenesis, ovulation and extracellular matrix breakdown. Aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5) have been identified in cartilage and are largely responsible for cartilage aggrecan breakdown. We have shown previously that synovium, the membrane lining diarthrodial joints, generates soluble aggrecanase activity. We report here the expression, localization and activity of ADAMTS-5 from human arthritic and bovine synovium. ADAMTS-5 was expressed constitutively in synovium with little or no transcriptional regulation by recombinant human interleukin-1a or all-trans-retinoate, factors previously shown to upregulate aggrecanase activity in cartilage. Aggrecanase activity generated by synovium in vitro and recombinant ADAMTS-5 cleaved aggrecan extensively, resulting in aggrecan fragments similar to those generated by chondrocyte-derived aggrecanases, and the activity was inhibited by heparin. ADAMTS-5 was immunolocalized in human arthritic synovium, where staining was mostly pericellular, particularly in the synovial lining and around blood vessels; some matrix staining was also seen. The possibility that synovium-derived ADAMTS-5 may play a role in cartilage aggrecan breakdown is discussed.Keywords: ADAMTS; aggrecanase; arthritis; synovium.The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases are a growing group of recently identified metallopeptidases related to the ADAMs (a disintegrin and metalloproteinase) [1]. They are classified in the Merops database of peptidases as members of subfamily B (the adamalysin subfamily) of family M12 in clan MA [2]. So far, nine mammalian ADAMTS proteinases have been identified [3]. They, unlike most ADAMs, do not possess an epidermal growth factor repeat domain or transmembrane domain but instead have a thrombospondin type I motif, a cysteine-rich spacer region and usually one or more C-terminal thrombospondin submotifs [4]. The thrombospondin type I repeats in thrombospondins 1 and 2 possess affinity for heparin and other sulfated glycosaminoglycans (sGAGs) as well as fibronectin and also contain cell adhesion sequences [5±7]. ADAMTS enzymes are therefore soluble proteins that may become incorporated into the extracellular matrix (ECM) after secretion, as is the case for ADAMTS-1 [8]. They may be activated during secretion through furin cleavage and release of the propeptide [9]. ADAMTS proteinases have been implicated in a wide range of ECM-degrading events [1,10±17]. For many of the ADAMTS proteinases however, biological functions remain to be assigned [3,18]. Two members, ADAMTS-1 and -8 have also been shown to possess potent antiangiogenic properties [19].Aggrecan, a large aggregating proteoglycan, is together with type II collagen the major constituent of articular cartilage. The type II collagen fibres provide the cartilage with tensile strength and agg...

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