rev:June 3, 1997

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INTERLEUKIN 18:  BACKGROUND INFORMATION

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INTERLEUKIN IL-18 (IGIF)

Interleukin-18 (IL-18), also known as interferon-gamma inducing factor (IGIF), is a pleiotropic cytokine, which like interleukin-12 (IL-12), seem to play an important role in the development of T helper type 1 (Thl) cells which are required for cell-mediated immune response. IL-18 was first isolated from the livers of mice that were previously injected with heat-killed Propionibacterium acnes (P.acnes), and then challenged with lipopolysaccharide (LPS) to induce toxic shock (1). Subsequently, a full length cDNA clone of IL-18 was obtained and its sequence revealed a precursor polypeptide (Pro IL-18) of 192 amino acids with an unusual leader sequence of 35 amino acids. The mature form of IL-18 is a polypeptide constructed from 157 amino acids and exhibits biological activities in the monomeric form (2). IL-18 is produced by activated blood monocytes and tissue macrophages such as Kupffer cells, and acts primarily as a co-stimulant for Th1 cells, inducing production of IFN-y, IL-2 and GM-CSF, stimulating IL-2R a-chain expression and Th1 cell proliferation.

Additionally, it has been reported that IL-18 enhances allospecific CTL activity in vitro, and like IL-12 it augments cytotoxic NK cell activity and inhibits production of IL-10 (but not of IL-4( (3,3). Recently, it has been demonstrated that IL-18 exhibits biological activity  that is totally independent of IFN-g production. Udagawa and co-workers have shown that IL-18 produced by osteoblastic stromal cells acts via GM-CSF and not via IFN-g to inhibit osteoclast formation (5).

Although IL-18. and IL-12 share the capacity to induce IFN-g production by activated Th1 cells, their induction pathways seem to be independent, since neutralizing antibodies to IL-12 do not block IFN-g production induced by IL-18 and vice versa. Also, IL-18 which is capable of inducing 2-5 times more IFN-g than optimal doses of IL-12, will augment more IFN-g even in the presence of  saturated amounts of IL-12 (4).

The human and murine IL-18 genes encode polypeptide precursors of 193 and 192 amino acids, respectively, which share 65% amino acid sequence homology. Interestingly, these precursor proteins lack the putative hydrophobic signal peptide necessary for secretion, but do contain an IL-1B signature-like sequence with a cleavage site after Asp 35. In the case of IL-1B it was clearly demonstrated that the 31 kDa inactive precursor is processed by a specific protease, interleukin-1B converting enzyme (ICE), that cleaves the precursor between Asp116 and Ala 117 releasing the 153 carboxyl-terminal amino acids that constitute the mature and active IL-1B (6). The ICE-like recognition site in the sequences of human and murine pro IL-18 led Yong Gu and co-workers to investigate the possible involvement of ICE-like proteases in the processing of pro IL-18 (7). Using recombinant pro IL-18 and recombinant human ICE in vitro, as well as COS cells co-expressing pro IL-18 and ICE, they have found that ICE can process the inactive pro IL-18 at the authentic processing site with high efficiency, thereby activating IL-18 and facilitating its export.The ICE-IL-18 pathway of IFN-g production was further supported by the finding that IFN-g and IL-18 were diminished in the sera of ICE-deficient mice exposed to P. acnes and LPS (7). This, together with the findings that ICE-deficient mice as well as mice lacking IFN-g or its receptor are resistant to septic shock induced by endotoxin (8,9) suggest that IL-18 plays a central role in inducing this type of septic shock. Supporting this view is the observation that neutralizing anti-IL-18 can prevent LPS-induced hepatic injury in P. acnes primed mice (2).

The range of IL-18 activities reported to date suggest that this novel cytokine plays an important regulatory role in cell-mediated immunity against foreign pathogens and perhaps also against tumor cells. Its availability as a pure and fully biologically active preparation should facilitate further exploration into the mechanisms that govern the immune system.

REFERENCES:

(1) H. Okamura et. al., Infect.Immun.,63,396 (1995).

(2) H. Okamura et. al., Nature, 378,88(1995).

(3) S. Ushio et. al., J. of Immuno., 156,4274 (1996).

(4) K. Kohno et. al., J. of Immun., 158,1541 (1997).

(5) N. Udagawa et. al., J.Exp. Med., 185,1005 (1997).

(6) D.P. Cerretti et. al.,Science, 256,97 (1992).

(7) Y. Gu et. al., Science 275,206 (1997).

(8) K. Kuida et. al., Science 267,2000 (1995).

(9) P. Li et. al., Cell, 80,401 (1995).

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