IL1 p Versus Il1 a

Since the above studies provide evidence that blocking IL-1 in disease is a sensible strategy, the next question is how much of the effectiveness of IL-1Ra in animal models as well as in human disease is due to blocking IL-1p compared to blocking IL-1 a? In humans, IL-1 a does not circulate during various disease states compared to IL-1 p. Unlike ICE, it is necessary to activate a nonspecific, membrane-bound protease, calpain, by calcium for the cleavage of proIL-1a (30). Calpain appears to be the protease that cleaves proIL-1a

Table 1 A Comparison of IL-1a and IL-1ß

IL-1a

proIL-1a is active

Active membrane is IL-1a

Mature IL-1a does not circulate

Nuclear localization

Intracellular role for proIL-1a

Neutralizing autoantibodies

Calpain cleavage proIL-1a

No disease link with calpain expression

No correlation

IL-1a KO mice normal

Anti-IL-1a ineffective in CIA

IL-1a expression in AML absent

No data

No data

No data proIL-1P is inactive Membrane IL-1P not observed mature IL-1P circulates No nuclear localization No intracellular role for proIL-1P Non-neutralizing autoantibodies ICE and PR-3 cleavage of proIL-1P Disease link with ICE expression Correlation with bone resorption

IL-1 P KO resistant to disease Anti-IL-1P effective in CIA IL-1P expression in AML present

ICE inhibition l brain ischemia ICE inhibition l AML proliferation ICE anti-sense l AML proliferation and results in secretion. However, unlike IL-1P, proIL-1a is active, and hence the role of any protease in conferring biological activity is questionable.

Nevertheless, IL-1a is found in tissues, particularly intracellularly. It has been speculated that the biological role for IL-1a in disease is as a membrane-bound cytokine. Indeed, membrane-bound IL-1 activity has consistently been IL-1 a, not IL-1 p. IL-1P is secreted, whereas IL-1 a remains biologically active as a cell-associated cytokine (31,32). Unlike IL-1P, normal skin and epithelial cells contain IL-1 a. Also, autoantibodies to IL-1 a are common and many are neutralizing antibodies (33).

IL-1 a appears to be involved with nuclear location and has a role in intracellular events, whereas IL-1P has no role in such events. For example, proIL-1a has a strong nuclear localization sequence and, when overexpressed, increases maligant transformation (34,35). Antisense DNA to IL-1 a reduces cell death in endothelial cells (36,37). Thus, IL-1 a appears to act as an intracellular growth factor. Differences in IL-1 a versus IL-1P are shown in Table 1.

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