A human myelomonocytic cell line, U937, produced an interleukin-1 (IL-1) receptor antagonist protein (IRAP) which was purified and partially sequenced. A complementary DNA coding for IRAP was cloned and sequenced. The mature translation product of the cDNA has been expressed in Escherichia coli and was an active competitive inhibitor of the binding of IL-1 to the T-cell/fibroblast form of the IL-1 receptor. Recombinant IRAP specifically inhibited IL-1 bioactivity on T cells and endothelial cells in vitro and was a potent inhibitor of IL-1 induced corticosterone production in vivo.

We studied a family in which two infants had died with massive venous thrombosis shortly after birth. Protein C antigen was undetectable by immunologic assays of plasma available from one infant. (Protein C is a potent naturally occurring anticoagulant that inactivates activated coagulation factors V and VIII). The parents, who were first cousins, both had partial protein C deficiency. Reduced protein C levels were also observed in 12 of 25 additional family members. None of the partially deficient family members (age range 4 to 70 years) had thrombotic episodes. Our data support the view that hereditary protein C deficiency is an autosomal disorder in which the homozygous state may be manifested by the virtual absence of plasma protein C and by fatal thrombosis in the neonatal period.

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Objective. To investigate the anti-arthritic effect of recombinant human interleukin-1 receptor antagonist protein (IRAP) in two experimental models of arthritis.Methods. Recombinant IRAP was administered daily to mice with type I1 collagen-induced arthritis (CIA) or with antigen-induced arthritis (AIA) provoked by methylated bovine serum albumin (mBSA). Disease incidence and severity were assessed by a clinical index and histologic features. Serum antibody to type I1 collagen, spleen cell proliferation to mBSA, and anti-IRAP antibodies were measured as indices of immune function.Results. IRAP reduced the incidence and delayed the onset of CIA and suppressed the antibody response to type I1 collagen. In contrast, IRAP did not affect the pathogenesis of AIA and had no effect on either humoral or cellular immune responses to mBSA in arthritic mice.Conclusion. These observations suggest that interleukin-1 may play a prominent role in the development of some, but not all, forms of arthritis.Interleukin-1 (IL-1) is present in the synovial fluid of rheumatoid arthritis (RA) patients (1-3). In approximately 40% of joint fluids from patients with RA, osteoarthritis, and miscellaneous connective tis-

The objective of these studies was to characterize the IL-1 inhibitory activity present in normal and psoriatic epidermis from clinically stable lesions. Fractionation of normal epidermal cytosol on a molecular sizing column failed to reveal the presence of IL-1 inhibitory bioactivity. However, specific ELISAs indicated that both the IL-1 receptor antagonist (IL-lra) and ILla were present in overlapping peaks. Further fractionation of the normal epidermal cytosol by anion exchange chromatography separated these two molecules, revealing the IL-1 inhibitory bioactivity ofthe IL-lra molecule. Similar studies on psoriatic epidermal cytosol indicated the presence of IL-1 inhibitory bioactivity and IL-lra protein. The IL-1 inhibitory bioactivity of both normal and psoriatic cytosol was neutralized by a mAb specific for IL-lra. The ratio of IL-lra to IL-la proteins was significantly increased in involved psoriatic skin compared with normal skin. By Western blot analysis this IL-lra was 20 kD, slightly larger than monocyte-derived IL-lra and equivalent to an intracellular variant of IL-lra expressed by keratinocytes. Polymerase chain reaction indicated the presence of mRNA for both forms of IL-lra in normal epidermis, with both forms increased in psoriatic-involved skin. Immunofluorescence studies revealed the IL-lra protein to be concentrated in the stratum granulosum of normal skin and in the basal-midbasal layers of psoriatic epidermis. These results suggest that the balance between intracellular IL-lra and IL-la may be an important influence on keratinocyte growth and/or differentiation, as well as on the inflammatory potential of IL-1 in injured skin. (J. Clin. Invest. 1992. 90:571-583.)