Macrophage Regulation

For this article, Nadia S. Halim interviewed Christopher K. Glass, professor of cellular and molecular medicine at the University of California, San Diego. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. M. Ricote, A.C. Li, T.M. Willson, C.J. Kelly, and C.K. Glass, "The peroxisome proliferator-activated receptor-g is a negative regulator of macrophage activation," Nature, 391:79-82, Jan.

May 29, 2000
Nadia Halim

For this article, Nadia S. Halim interviewed Christopher K. Glass, professor of cellular and molecular medicine at the University of California, San Diego. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age.

M. Ricote, A.C. Li, T.M. Willson, C.J. Kelly, and C.K. Glass, "The peroxisome proliferator-activated receptor-g is a negative regulator of macrophage activation," Nature, 391:79-82, Jan. 1, 1998. (Cited in more than 175 papers since publication)

Macrophages, immune system scavengers, guard against disease by ingesting particulate material, including microbes. While studying how the body regulates these cells, Christopher K. Glass, professor of cellular and molecular medicine, and his lab at the University of California, San Diego, found that activated macrophages express high levels of the PPAR-g receptor. Because this protein belongs to a family of nuclear receptors that control gene transcription, they had a good hunch that PPAR-g was involved in macrophage regulation. "But we had no target genes [that were affected by the receptor] and no ligands [corresponding to the receptor] at the time," says Glass.

They were able to push the science forward when researchers identified ligands for the PPAR-g receptor: a class of synthetic antidiabetic drugs (thiazolidinediones) and a prostaglandin D2 metabolite (15d-PGJ2) produced by the human body. Prostaglandin D2 belongs to a group of fatty acids that regulate many different physiological functions. Interestingly, macrophages and antigen-presenting cells express the enzyme that synthesizes 15d-PGJ2. Based on this information, Glass proposed a system in which macrophages not only expressed PPAR-g receptors, but also generated the ligands for them.

His lab found that PPAR-g inhibited several genes in activated macrophages treated with either natural or synthetic ligands. "PPAR-g inhibits gene expression in a similar manner to other nuclear receptors, by antagonizing the activities of AP-1, STAT, and NF-*B," explains Glass. These three classes of transcription factors play general roles in regulating inflammatory responses.

This paper suggested that PPAR-g ligands could be used to treat inflammatory diseases such as atherosclerosis and rheumatoid arthritis. In early stages of atherosclerosis, macrophages invade the artery wall and ingest cholesterol-laden lipoproteins. When they become engorged with cholesterol, they are called foam cells; in this form, they make up early atherosclerotic lesions. In rheumatoid arthritis, macrophages secrete a number of cytokines and enzymes, which leads to destruction of the joint space. The proposed role PPAR-g plays in inflammation was completely different from its established function in fat cell development and glucose metabolism, which may be one reason the paper has generated so much interest.

The PPAR-g story is just beginning to unfold. Thiazolidinediones are becoming drugs of choice for treating type 2 diabetes. "Some diabetics are taking a drug that is regulating the expression of PPAR-g in cells forming atherosclerotic lesions, the major cause of death in these patients," explains Glass. He adds, "A large percentage of citings may come from the atherosclerosis community because of the diabetes-atherosclerosis connection."


From left, Mercedes Ricote, Christopher K. Glass, and Andrew Li
It is still unclear whether thiazolidinedione-mediated regulation of gene expression in macrophages can prevent atherosclerotic lesions. The answer to this question will have an impact on virtually every major pharmaceutical company, because they are developing PPAR-g ligands for diabetes treatment. If the drugs in development are also useful in treating atherosclerosis, the market opens up to patients without diabetes. On the other hand, if they promote atherosclerosis, diabetic patients are in trouble. "The receptor is probably playing complex roles in the macrophage, both inhibiting inflammation and regulating genes that control foam cell formation. Based on preliminary results in animal models, I think the net effect on lesion development is inhibition," says Glass.

In their search for new PPAR-g ligands that are found in the human body, the group found cytokine IL-4 turns on PPAR-g.1 IL-4 is also known to turn on the 12/15-lipoxygenase enzyme, which metabolizes arachidonic acid into 15-HETE and linoleic acid into 13-HODE. They showed that PPAR-g and 12/15-lipoxygenase are required for IL-4 dependent activation of CD36, a type B scavenger receptor. Scavenger receptors on macrophages bind and internalize modified forms of low-density lipoprotein, which leads to foam cell formation. For macrophages treated with IL-4, PPAR-g ligands are products of 12/15-lipoxygenase. "That was a pretty significant finding because it was the first pathway nailed down for regulated production of PPAR ligands," says Glass.

1. J.T. Huang et al., "Interleukin-4-dependent production of PPAR-g ligands in macrophages by 12/15-lipoxygenase," Nature, 400: 378-82, July 22, 1999.