The cell-killing effects of the cytokines TNF-alpha and FasL are mediated by the distinct cell-surface receptors TNFR1, TNFR2 and Fas (also known as CD95/APO-1), which are all members of a receptor superfamily that is important for regulating cell survival. The cytoplasmic regions of TNFR1 and Fas contain a conserved 'death' domain which is an essential component of the signal pathway that triggers apoptosis and activation of the transcription factor NF-kappaB (refs 5,6). Here we report the isolation of a 54K receptor that is a new member of the TNFR superfamily, using the death domain of TNFR1 in a yeast two-hybrid system. This protein, WSL-1, is most similar to TNFR1 itself, particularly in the death-domain region. The gene wsl-1 is capable of inducing apoptosis when transfected into 3T3 and 293 cells, and can also activate NF-kappaB in 293 cells. Like TNFR1, WSL-1 will homodimerize in yeast. WSL-1 also interacts specifically with the TNFR1-associated molecule TRADD. The tissue distribution is very restricted and significantly different from that of Fas and TNFR1.

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Kallikrein type serine proteases, KLK8/neuropsin, KLK6, and KLK7, have been implicated in the proliferation and differentiation of epidermal keratinocytes and in the pathogenesis of psoriasis. However, their mechanistic roles in these processes remain largely unknown. We applied 12-O-tetradecanoylphorbol-13-acetate on the wild type (WT) and the Klk8 gene-disrupted (Klk8 ؊/؊ ) mouse skin, inducing keratinocyte proliferation similar to the human psoriatic lesion. Klk8 mRNA as well as Klk6 and Klk7 mRNA were up-regulated after 12-O-tetradecanoylphorbol-13-acetate application in the WT mice. In contrast, Klk8؊/؊ mice showed minimum increases of Klk6 and Klk7 transcripts, the proteins, and enzymatic activities. Relative to the WT, the Klk8 ؊/؊ skin showed less proliferation and an increase in the number of cell layers in the stratum corneum. However, overexpression of Klk8 by adenovirus vector in knock-out keratinocytes did not result in an increase in Klk6 or Klk7 mRNA. The inefficient cleavage of adhesion molecules DSG1 and CDSN in Klk8 ؊/؊ skin contributes to a delay in corneocyte shedding, resulting in the hyperkeratosis phenotype. We propose that in psoriatic lesion, KLK8 modulates hyperproliferation and prevents excessive hyperkeratosis by shedding the corneocytes.

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Oligodendrocytes are important for not only nerve conduction but also central nervous system (CNS) development and neuronal survival in a variety of conditions. Kallikrein-related peptidase 6 (KLK6) is expressed in oligodendrocytes in the CNS and its expression is changed in several physiological and pathological conditions, especially following spinal cord injury (SCI) and experimental autoimmune encephalomyelitis. In this study, we investigated the functions of KLK6 in oligodendrocyte lineage cell development and the production of myelin proteins using KLK6-deficient (KLK6(-/-)) mice. KLK6(-/-) mice were born without apparent defects and lived as long as wild-type (WT) mice. There was no significant difference in the numbers of oligodendrocyte precursor cells and mature oligodendrocytes in the adult naive spinal cord between WT and KLK6(-/-) mice. However, there were fewer mature oligodendrocytes in the KLK6(-/-) spinal cord than in the WT spinal cord at postnatal day 7 (P7). Expression of myelin basic protein (MBP) and oligodendrocyte-specific protein/claudin-11, major myelin proteins, was also decreased in the KLK6(-/-) spinal cord compared with the WT spinal cord at P7-21. Moreover, after SCI, the amount of MBP in the damaged spinal cords of KLK6(-/-) mice was significantly less than that in the damaged spinal cords of WT mice. These results indicate that KLK6 plays a functional role in oligodendrocyte development and the expression of myelin proteins.