A chemoattractant cytokine associated with granulomas in tuberculosis and silicosis

A chemoattractant cytokine associated with granulomas in tuberculosis and silicosis

^*Whitehead Institute for Biomedical Research, Nine Cambridge Center, and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142; ^†Infectious Disease Unit, Massachusetts General Hospital, Fruit Street, Boston, MA 02114; ^§Pulmonary Center, Boston University School of Medicine, 80 East Concord Street, Boston, MA 02188; and ^¶Boston Veterans Affairs Medical Center, 150 South Huntington Avenue, Boston, MA 02130

Abstract

Chronic inflammation and granuloma formation are associated with mononuclear cell infiltrates and are characteristic pathologic responses in tuberculosis. To identify host cell genes involved in tuberculous pathology, we screened macrophage cDNA libraries for genes induced by mycobacterial infection. One gene isolated in this screen, osteopontin (also known as early T lymphocyte activation protein 1 or Eta-1), was of particular interest because it is a cytokine and macrophage chemoattractant. Further study revealed that Mycobacterium tuberculosis infection of primary human alveolar macrophages causes a substantial increase in osteopontin gene expression. Osteopontin protein was identified by immunohistochemistry in macrophages, lymphocytes, and the extracellular matrix of pathologic tissue sections of patients with tuberculosis. Increased osteopontin expression also was found to be associated with silicosis, another granulomatous disease. The association of osteopontin with granulomatous pathology, together with the known properties of the protein, suggest that osteopontin may participate in granuloma formation. The strategy of identifying host genes whose expression is altered by infection thus can provide valuable clues to disease mechanisms and will be increasingly valuable as additional human genome sequences become available.

Footnotes

↵ ‡ Present address: Biology Department, Bemidji State University, 1500 Birchmont Drive, NE, Bemidji, MN 56601.
↵ ‖ To whom reprint requests should be addressed.
Stanley Falkow, Stanford University, Stanford, CA
ABBREVIATIONS:

BCG,

bacillus Calmette–Guérin;

MIP-1α,

macrophage inflammatory protein 1-α