A newly developed ELISA was used to detect and quantify the presence of a soluble form of intercellular adhesion molecule-1 (sICAM-1) in the circulation of healthy individuals compared with patients with psoriasis vulgaris. Seventeen psoriatic patients were studied. The extent of skin lesions was rated by the psoriasis area and severity index (PASI). Seventeen age- and sex-matched healthy individuals served as controls. Serum levels were measured by an ELISA technique utilizing an anti-ICAM-1 murine monoclonal antibody bound to the solid phase, and a second, peroxidase-conjugated monoclonal antibody reacting with sICAM-1. Serum levels in controls were 358.8 +/- 87.9 ng/ml sICAM-1, and 480.5 +/- 133.6 ng/ml in psoriatics (mean +/- SD; P = 0.02). In psoriasis, sICAM-1 levels were found to be directly proportional to the PASI score (y = 363.002 + 8.525x, R = 0.55, P = 0.021). These data suggest that the concentration of sICAM-1 in serum increases during psoriatic inflammation. The origin and function of sICAM-1 in psoriasis remain to be defined.

Summary: Several methyl 17ß-carboxyester derivatives of natural and fluorinated glucocorticoids were synthesized in order to compare their potency to compete for [ 3 H]dexamethasone binding sites in human spieen tumour cytosols (äs a source of large quantities of white blood cells) with their potency to inhibit phytohaemagglutinin-induced blastogenesis of normal human peripheral lymphocytes. The 17ß-carboxylic acids neither show binding activity nor Inhibition of blastogenesis. Methylation partially restores the binding capacity and the intensity of this effect depends on the kind of ring substitütions. The sequence of binding potency is identical compared to that of parent steroids and was found to be in the following order: desoximetasone > dexamethasone > corticosterone > Cortisol > progesterone > 17-hydroxyprogesterone. The phytohaemagglutinin-induced Stimulation of [ 3 H]thymidine incorporation resembles the order of binding potency. The methyl 17ß-carboxyester derivatives of progesterone, 17-hydroxyprogesterone and betamethasone are inactive. The N-benzyl 17ß-carboxamide analogs of dexamethasone and betamethasone behave like their corresponding carboxyesters, suggesting an important influence of the side chain conformation of 17ß-carboxyl derivatives on glucocorticpid receptor binding.

Summary: Several novel 17ß-carboxamide analogues of dexamethasone were synthesized. The common precursor, 9-fluoro-16a-methyl-llß,17-dihydroxy-3-oxo-l,4-androstadiene-17ß-carboxylic acid, did not bind to the glucocorticoid receptors of rat liver and human spieen tumours. In addition, no Inhibition of the mitogen-induced blastogenesis of cultured human peripheral lymphocytes was observed. The 17ß-carboxamide analogues, however, bound with similar affinities to the glucocorticoid receptors of both tissues. They inhibited the mitogen-induced blastogenesis of peripheral lymphocytes, showing the same potency and same order of binding affinity äs the natural glucocorticoids. 17ß-Carboxamid-Steroide: Hochwirksame Inhibitoren der phytohämagglutinin-induzierten Blastogenese normaler peripherer menschlicher LymphocytenZusammenfassung: Es wurden mehrere neuartige 17ß-Carboxamid-Analoga des Dexamethasons synthetisiert. Die Ausgangsverbindung, 9-Fluor-16cc-methyl-11 ß, 17-dihydroxy-3-oxo-1,4-androstadien-17ß-carbonsäure, zeigte keine Bindung an Rattenleber-oder menschliche Milztumor-Glucocorticoidrezeptoren. Ebenso konnte keine Inhibition der mitogen^-induzierten Blastogenese normaler menschlicher Lymphocyten gezeigt werden. Im Gegensatz dazu banden die 17ß-Carboxamid-Analoga mit ähnlicher Affinität an die Glucocorticoidrezeptoren beider Gewebe. Ihre Potenz, die mitogen-induzierte Blastogenese der Lymphocyten zu hemmen, war von der natürlicher Glucocorticoide nicht zu unterscheiden und korrespondierte mit der jeweiligen Affinität zum Rezeptor.

We examined whether preincubating polymorphonuclear leukocytes (PMN) with TNF alpha would result in an enhanced respiratory burst upon subsequent stimulation by various agents. Bacterial lipopolysaccharide (LPS), a known primer of PMN, was used as control. We found that both LPS (0.01 to 10.0 microgram/ml) and recombinant TNF alpha (0.001 to 1.0 microgram/ml) act as direct stimulants of PMN as measured by chemiluminescence. Sixty minutes of preincubation of PMN with 1 microgram/ml TNF alpha or 10 micrograms/ml LPS resulted in similar priming for the respiratory burst elicited by opsonized zymosan, phorbol myristate acetate, zymosan, zymosan-activated serum, aggregated immunoglobulin, and f-met-leu-phe (FMLP) depending on the method of measurement used, i.e., chemiluminescence, production of O2-, and H2O2. Priming with TNF alpha for an enhanced response to stimulation by FMLP could be abrogated by anti-TNF alpha antibody. Cell-surface receptor numbers and binding-affinity constants for FMLP remained stable under conditions leading to priming. We conclude that TNF alpha is able to prime PMN for an enhanced respiratory burst to a similar extent as with LPS. Because PMN cell-surface receptors for FMLP are unaltered by priming, the enhanced respiratory burst seems to be due to changes in intracellular metabolism.

During a therapeutic trial to treat psoriasis with either etretinate or cyclosporin A (CyA) we measured the respiratory burst activity of polymorphonuclear leukocytes (PMN). Six patients received 0.5-0.75 mg/kg etretinate and 14 patients 2.5-5.0 mg/kg CyA over a period of 10 weeks. The extent of psoriasis was graded by the psoriasis area-and-severity index (PASI score). The respiratory burst of PMN isolated from the peripheral blood was measured employing luminol-enhanced chemiluminescence at weeks 0, 3 and 10 and compared with that of 26 healthy control individuals. PMN were stimulated with zymosan particles, aggregated immunoglobulin (aggIg) and concanavalin A (ConA). Both treatment regimens improved psoriasis; at 10 weeks there was an approximate 40% PASI score reduction under etretinate and an 80% improvement under CyA. Before treatment the respiratory burst was abnormally high under stimulation with the three stimuli in patients (p = 0.021 to less than 0.0001). After 3 to 10 weeks PMN activity normalized in all patients and even tended to drop below values correlating with an improvement in skin lesions. We conclude that the elevated respiratory burst of PMN in psoriasis normalizes under treatment with both etretinate and CyA.