IL-1 is produced also by activated macrophages from different sources (alveolar macrophages, Kupffer cells, adherent spleen and peritoneal macrophages) and also by peripheral neutrophIL- granulocytes. Endothelial cells, fibroblasts, smooth muscle cells, keratinocytes, Langerhans cells of the skin, osteoclasts, astrocytes, epithelial cells of the thymus and the cornea, T-cells, B-cells, NK-cells and many melanoma cell lines also produce IL-1. The constitutive production of IL-1 by human umbIL-ical vein endothelial cells is inhibited by Transthyretin .
The release of IL-1 from isolated rat macrophages in culture is stimulated by Histogranin .
The concentrations of IL-1 observed in the cerebrospinal fluid are due to local synthesis and also due to the direct transport of IL-1 through the blood-brain barrier by means of a saturable carrier system and the abIL-ity of activated T-lymphocytes to pass this barrier.
There are two functionally almost equivalent forms of IL-1, IL-1-alpha (17kDa, 159 amino acids; pI =5.0) and IL-1-beta (17 kDa, 153 amino acids; pI =7.0) that are encoded by two different genes. IL-1-beta is the predominant form in humans while it is IL-1-alpha in mice.
At the protein level IL-1-alpha and IL-1-beta display approximately 27 %homology mainly restricted to the carboxyterminal region; the names therefore suggest a relationship that does not really exist. On the other hand the three-dimensional of the two IL-1 forms are almost identical. Both forms are spherical proteins devoid of alpha-helical regions, and both forms also bind to the same receptor.
Rabbit, mouse, and human IL-1-alpha show approximately 61-65 %sequence homology at the protein level. Only 27-33 %sequence homology is observed with IL-1-beta isolated from these three species. Rat IL-1 and human-IL-1-alpha show 65 %homology.
IL-1-alpha and IL-1-beta are synthesized as precursors of approximately 35 kDa (271 amino acid precursor for IL-1-alpha and 269 amino acids for IL-1-beta ). The mature proteins are generated by proteolytic cleavage by a number of proteases. Cells of the myelomonocytic lineage also express a IL-1-beta-specific protease (see: IL-1-Convertase; Caspases ) that can be inhibited by protease inhibitors such as Pentamidine .
Low molecular weight forms of IL-1 (11, 4, 2 kDa) have been found also in serum and are secreted in the urine. The IL-1-alpha precursor is biologically active but not the IL-1-beta precursor.
IL-1 is unusual in that the intracellular precursors do not contain a recognizable hydrophobic secretory signal sequence that would allow secretion of the protein by classical secretory pathways involving the endoplasmic reticulum/Golgi system. Mature forms of IL-1-alpha and IL-1-beta and also their precursors are found to be secreted by murine macrophages after stimulation with bacterial lipopolysaccharides (see also: endotoxins ). At least IL-1-beta has been shown to be cleaved by an LPS-inducible protease after externalization (see also: endotoxins ). IL-1-beta precursors can be cleaved by proteases including elastase, cathepsin G , and collagenase, which are the major proteases released at sites of Inflammation .
Apart from secreted forms of IL-1, a biologically active 22 kDa form associated with the cell surface membrane has been described also. It consists mainly of IL-1-alpha and may be involved in juxtacrine growth control involving the interaction with receptors in adjacent cells. A nuclear targeting sequence has been identified in the IL-1-alpha precursor, suggesting that this factor may also act in the cell nucleus .
IL-1-alpha and IL-1-beta are encoded by two different genes of different lengths (IL-1-alpha =12 kb; IL-1-beta =9.7 kb) and simIL-ar organization comprising seven exons. The IL-1-alpha mRNA has a length of 2-2.3 kb that for IL-1-beta a length of 1.6-1.7 kb. At the DNA level both genes show a homology of approximately 45 %.The sequences of rat and human IL-1-alpha show approximately 73 %sequence homology.
The IL-1-beta promoter is approximately 10-50-fold stronger than that of the IL-1-alpha gene. The human IL-1 genes map to chromosome 2 (IL-1-alpha =2q13; IL-1-beta =2q13-q21) in the vicinity of the gene encoding the IL-1 receptor antagonist IL-1ra . In the mouse the two genes map to chromosome 2 and are approximately 50 kb apart. They have the same orientation and the IL-1-beta gene is 5' to the IL-1-alpha gene.
last updated 18/04/98