Cysteine proteases are involved in diverse cellular processes ranging from the processing of precursor proteins to intracellular degradation. They may induce vascular permeability through activation of the kallikrein/kinin pathway, complex with various hemagglutinins, activate complement components and destroy serpins. Their endopeptidase activity and "trypsin-like" specificity leads to the speculation that there are many specialized cysteine protease molecules found in various human cells and tissues.
Cysteine proteases are known to be produced by monocytes, macrophages and other cells of the immune system. These cells migrate to sites of inflammation and in their protective role secrete various molecules which clean up damaged tissue. Under other conditions, these same cells may overproduce the same molecules and cause tissue destruction. This is the case in autoimmune diseases such as rheumatoid arthritis, when the secretion of the cysteine protease, cathepsin C, degrades collagen, laminin, elastin and other structural proteins found in the extracellular matrix of bones. Bone weakened by such degradation is more susceptible to tumor invasion and metastasis.
The novel human cysteine protease of this application was first identified among the sequences of a cDNA library made from human adrenal glands.
Human adrenal glands are cap-like structures located above each kidney. Each gland consists of the adrenal medulla and the adrenal cortex. The adrenal medulla is made up of chromaffin tissue and mainly secretes norepinephrine (NE) and epinephrine (E). Stimulation of the sympathetic nerves to the adrenal medulla releases these two catecholamines into the blood. NE constricts blood vessels, stimulates cardiac activity, inhibits the gastro-intestinal tract, and dilates the pupils of the eyes. Epinephrine triggers almost the same responses, but it has a stronger effect on cardiac activity and a weaker effect on blood vessels. NE and E supplement the effects of the sympathetic nervous system but appear to have little effect on its function.
The adrenal cortex uses cholesterol to produce a large number of corticosteroids which display hormonal activity. The outer layer of the adrenal gland mainly produces the mineralocorticoid, aldosterone. The stimulatory and inhibitory regulation of aldosterone secretion is governed by potassium level, renin-angiotensin interactions, and secretion of adrenocorticotrophic hormone (ACTH), dopamine, serotonin, and .beta.-endorphin. Aldosterone regulates extracellular fluid volume and sodium/potassium balance by interacting with type-I mineralocorticoid receptors in target tissues such as the kidney, salivary gland, and intestinal mucosa.
The inner layers of the adrenal gland are sites of glucocorticoid and androgen, estrogen and progesterone biosynthesis. The principal glucocorticoid is cortisol which functions in the regulation of protein, carbohydrate, lipid, and nucleic acid metabolism, acts as an anti-inflammatory, and plays a biofeedback role in suppressing endocrine functions. Androgen, secreted under the regulation of ACTH, is responsible for initiating the development of secondary sexual characteristics (in both sexes), of sex organs in the male, and for maintaining lifelong spermatogenesis.
Conditions, diseases and disorders of the adrenal gland include chromaffin cell tumors, which are part of the multiple endocrine neoplasia syndromes; Sipple's syndrome, which may be found alone or associated with medullary thyroid carcinoma and parathyroid adenomas; adrenal virilism; Cushing's syndrome; Conn's syndrome; Addison's disease, which is a primary adrenocortical insufficiency; secondary adrenocortical insufficiency, and adrenal adenomas, which include benign adrenal cysts, nonfunctional adrenal carcinoma, and tuberculosis of the adrenal gland.
The adrenal gland and its diseases are reviewed, inter alia, in Guyton AC (1991) Textbook of Medical Physiology, W B Saunders Co, Philadelphia Pa.; Isselbacher, K J et al (1994) Harrison's Principles of Internal Medicine, McGraw-Hill New York N.Y.; The Merck Manual of Diagnosis and Therapy (1992) Merck Research Laboratories, Rahway N.J.; and Goodman A G et al. (1993) The Pharmacological Basis of Therapeutics, McGraw-Hill, New York N.Y.