Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia, and interleukin 6 production in vivo.

Abstract

SummaryThe role ofprostaglandin E 2 (PGE2) in the development of inflammatory symptoms and cytokine production was evaluated in vivo using a neutralizing anti-PGE2 monoclonal antibody 2B5. In carrageenan-induced paw inflammation, pretreatment of rats with 2B5 substantially prevented the development of tissue edema and hyperalgesia in affected paws. The antibody was shown to bind the majority of PGE 2 produced at the inflammatory site. In adjuvantinduced arthritis, the therapeutic administration of 2B5 to arthritic rats substantially reversed edema in affected paws. Anti-PGE2 treatment also reduced paw levels oflL-6 lq.NA and serum IL-6 protein without modifying tumor necrosis factor P, NA levels in the same tissue. In each model, the antiinflammatory efficacy of 2B5 was indistinguishable front that of the nonsteroidal antiinflammatory drug indomethacin, which blocked the production of all PGs. These results indicate that PGE 2 plays a major role in tissue edema, hyperalgesia, and IL-6 production at sites of inflammation, and they suggest that selective pharmacologic modulation of PGE 2 synthesis or activity may provide a useful means of mitigating the symptoms of inflammatory disease.

Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

“…Cyclooxygenases (COX) are intracellular proteins that catalyse the rate-limiting step in the synthesis of prostaglandins (PGs), a potent group of autocrine and paracrine lipid mediators (Mitchell et al, 1995;Smith et al, 1996;Chen et al, 2000) that are implicated in many normal cellular and pathophysiological processes (Mitchell et al, 1995;Portanova et al, 1996;Smith et al, 1996;Chen et al, 2000). Two forms of COX have been identified to date: the constitutively expressed form COX-1, and the inducible form COX-2.…”

Cyclooxygenase 2–derived prostaglandin E2 production by corticotropin‐releasing hormone contributes to the activated cAMP response element binding protein content in rheumatoid arthritis synovial tissue

“…Nonetheless, the Ͼ90% inhibition of IL-1␤-and CRH-stimulated PGE 2 production by selective COX-2 inhibitors is of particular interest, because in RA synovial tissue, PGE 2 production occurs exclusively via COX-2. PGE 2 plays a major role in tissue edema, hyperalgesia, and IL-6 production and has been specifically implicated in the symptoms of arthritis, including the erosion of cartilage and juxtaarticular bone in RA (15,16). In an animal model of polyarthritis, neutralizing PGE 2 with monoclonal antibodies reduced both the signs and levels of inflammatory markers of the disease, highlighting the significant contribution of PGE 2 to the pathogenesis of the disease (15).…”

“…PGE 2 plays a major role in tissue edema, hyperalgesia, and IL-6 production and has been specifically implicated in the symptoms of arthritis, including the erosion of cartilage and juxtaarticular bone in RA (15,16). In an animal model of polyarthritis, neutralizing PGE 2 with monoclonal antibodies reduced both the signs and levels of inflammatory markers of the disease, highlighting the significant contribution of PGE 2 to the pathogenesis of the disease (15). Despite the accumulating evidence to support the importance of PGE 2 in RA, the contribution of PGE 2 and individual PGE 2 receptors (EP 1 -EP 4 ) in the pathogenesis of arthritis has only recently been addressed (16).…”

“…Furthermore, PGE 2 is involved in the erosion of cartilage and juxtaarticular bone (11), stimulates the production of matrix metalloproteinases (12), contributes to angiogenesis (13), and inhibits apoptosis of T lymphocytes (14). Neutralizing antibodies against PGE 2 inhibit acute and chronic inflammation in the rat adjuvant arthritis model (15). PGE 2 exerts its actions by binding to 1, or a combination, of 4 subtypes of receptor (EP 1 , EP 2 , EP 3 , and EP 4 ).…”

Targeting sphingosine-1-phosphate for cancer therapy

“…By comparison with large protein ligands like VEGF (35 000 -44 000 Da), the lipid target, S1P, is a small molecule (379 Da) and, as a consequence, has only one epitope (i.e., the polar head group) to target for antibody recognition (inset of Figure 1). Unlike the successful work with anti-PGE2 mAbs (Portanova et al, 1996), academics and industry researchers have not been successful in developing mAbs that inhibit bioactive lysolipids like S1P and LPA with antibody specificity, affinity and other performance characteristics suitable for preclinical proof-ofconcept work. This leads one to argue that sphingomab may be a drug of an emerging discipline that may be termed lipidomicbased therapeutics.…”