The cytokine receptor CD137 is a member of the TNF receptor family and a potent T cell costimulatory molecule. Its ligand is expressed on antigen presenting cells as a transmembrane protein and it too can deliver signals into the cells it is expressed on (reverse signaling). In monocytes, immobilized CD137 protein induces activation, prolongation of survival and proliferation. Here we show that recombinant immobilized CD137 protein enhances migration of monocytes in vitro. Further, CD137 expression on spheroids leads to a significantly enhanced infiltration by monocytes. The migration-inducing activity of CD137 could be confirmed in vivo. Matrigel, which was coated with recombinant CD137 protein and was inserted into the flanks of mice attracted large numbers of monocytes and was heavily infiltrated by these cells. In vivo, expression of CD137 by blood vessel walls at sites of inflammation was detectable by immunohistochemistry. CD137 expression is inducible by proinflammatory cytokines in endothelial cells, suggesting that a physiological function of CD137 may be the facilitation of monocyte extravasation in inflammatory tissues.

CD137 (ILA/4-1BB) is a member of the tumor necrosis factor receptor family and regulates activation, proliferation and programmed cell death in T lymphocytes. Here we show the existence of a soluble form of CD137 (sCD137) of 16 kDa. sCD137 is released by activated lymphocytes, and in contrast to membrane-bound CD137, expression of sCD137 seems to be restricted to lymphocytes. sCD137 is generated by alternative splicing and two splice variants were identified. sCD137 is present at low levels in sera of some healthy donors (5/12; mean = 0.18 ng/ml) and is significantly enhanced in sera of patients with rheumatoid arthritis (12/12; mean = 3.58 ng/ml).

SUMMARYCD95 (APO-1/Fas) and CD137 (ILA/4-1BB) are members of the tumour necrosis factor receptor family, and both are involved in induction of apoptosis in lymphocytes. Contrary to the case of CD95, apoptosis by CD137 is caused by cross-linking of the respective ligand rather than the receptor. Nothing is known so far about the mechanism of CD137-induced cell death. Here, we show that immobilized CD137 protein induces expression of CD95 in resting primary T and B lymphocytes. However, induction of apoptosis by CD137 is independent of CD95, because: (1) antagonistic anti-CD95 antibody fragments do not block CD137-induced apoptosis; and (2) CD137, but not anti-CD95, can induce apoptosis in resting lymphocytes. INTRODUCTIONestablished tumours in mice by inducing a specific antitumour immune response.18 Induction of apoptosis has been documented for several memBidirectional transduction of signals exists for the CD137 bers of the tumour necrosis factor (TNF ) receptor family receptor/ligand system. While cross-linking of CD137 activates and different mechanisms have been identified.1-3 Typically, T lymphocytes, cross-linking of the CD137 ligand has the apoptosis is induced by cross-linking of receptors by trimerized opposite effect. This reverse signalling through the CD137 ligands, as shown for CD95 and TNF receptor I.4-6 In the ligand inhibits proliferation of T lymphocytes and induces case of the p75 nerve growth factor receptor, apoptosis can apoptosis.8 Reverse signalling through a CD137 ligand exists be induced by the unoccupied receptor and this activity is also for monocytes and in these cells cross-linking of CD137 suppressed by binding of the ligand to the receptor.7 A third ligand causes activation.19 mechanism is found in the case of CD137, where apoptosisThe human CD137 ligand is expressed constitutively by can be induced by cross-linking of the membrane-bound ligand monocytes, B cells and neuroblastoma cells and its expression by the CD137 receptor.8 is inducible in T lymphocytes.11 For the murine CD137 ligand CD137 (ILA/4-1BB) is a member of the TNF receptor constitutive expression was reported for bone marrow and family and was identified in screens for receptors expressed thymus, macrophages and B cells, and inducible expression on activated lymphocytes.9-11 CD137 is expressed by activated for T lymphocytes.20 The human and murine CD137 ligands lymphocytes and monocytes and expression in primary cells is display only 36% homology, compared to 70-80% of humanstrictly activation dependent.12 Soluble forms of CD137 are mouse interspecies homology for other TNF family members, generated by differential splicing and are present at enhanced implying the existence of yet other, unidentified CD137 ligands. concentrations in sera of patients with rheumatoid arthritis.13In fact, for the murine, but not for the human CD137, binding The gene for human CD137 resides on chromosome 1p36, in to extracellular matrix proteins has been shown.21,22 a cluster of related genes, and this chromosomal region isIn the presen...

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