Methods of modulating tumor necrosis factor .alpha.-induced expression of cell adhesion molecules

DETAILED DESCRIPTION OF THE INVENTION The present invention employs specific inhibitors of Ha-ras, c-raf and JNK2, members of the TNF-.
alpha.
signaling pathway, to modulate cell adhesion molecule expression.
These inhibitors can include monoclonal antibodies, peptide fragments, small molecule inhibitors and antisense compounds.
In a preferred embodiment, antisense compounds, particularly oligonucleotides, are used to modulate the function of nucleic acid molecules encoding Ha-ras, c-raf or JNK2, modulating the amount of protein produced and ultimately modulating the expression of cell adhesion molecules.
This is accomplished by providing oligonucleotides which specifically hybridize with nucleic acids, preferably mRNA, encoding Ha-ras, c-raf or JNK2.
This relationship between an antisense compound such as an oligonucleotide and its complementary nucleic acid target, to which it hybridizes, is commonly referred to as "antisense".
"Targeting" an oligonucleotide to a chosen nucleic acid target, in the context of this invention, is a multistep process.
The process usually begins with identifying a nucleic acid sequence whose function is to be modulated.
This may be, as examples, a cellular gene (or mRNA made from the gene) whose expression is associated with a particular disease state, or a foreign nucleic acid from an infectious agent.
In the present invention, the targets are nucleic acids encoding Ha-ras, c-raf or JNK2; in other words, a gene encoding Ha-ras, c-raf or JNK2, or mRNA expressed from the Ha-ras, c-raf or JNK2 gene.
mRNA which encodes Ha-ras, c-raf or JNK2 is presently the preferred target.
The targeting process also includes determination of a site or sites within the nucleic acid sequence for the antisense interaction to occur such that modulation of gene expression will result.
In accordance with this invention, persons of ordinary skill in the art will understand that messenger RNA includes not only the information to encode a protein using the three letter genetic code, but also associated ribonucleotides which form a region known to such persons as the 5'-untranslated region, the 3'-untranslated region, the 5' cap region and intron/exon junction ribonucleotides