Milk fat globule EGF factor 8 in the serum of human patients of systemic lupus erythematosus.
Mouse milk fat globule epidermal growth factor 8 (MFG-E8), which is secreted by a subset of activated macrophages, binds to apoptotic cells by recognizing phosphatidylserine and promotes their engulfment. Many apoptotic cells are left unengulfed in the germinal centers of the spleen in MFG-E8(-/-) mice, and these mice develop an autoimmune disease resembling human systemic lupus erythematosus (hSLE). Here, we report that hMFG-E8 bound to phosphatidylserine and an integrin alpha(v)beta(3) complex. Increasing concentrations of MFG-E8 generated a bell-shaped response curve for the efficiency of phagocytosis. That is, in NIH3T3 and MFG-E8(-/-) thioglycollate-elicited peritoneal macrophages that do not express MFG-E8, hMFG-E8 enhanced engulfment at low concentrations but inhibited it at high concentrations. On the other hand, hMFG-E8 dose-dependently inhibited the engulfment of apoptotic cells by MFG-E8(+/+) thioglycollate-elicited peritoneal macrophages, indicating that an excess of MFG-E8 has an inverse effect on the engulfment of apoptotic cells. To investigate the role of MFG-E8 in human disease, we generated two mAb against MFG-E8 and screened human blood samples for MFG-E8 using an ELISA. We found that some childhood-onset and adult SLE patients carried a significant level of MFG-E8 in their blood samples. These results suggested that the aberrant expression of MFG-E8 is involved in the pathoetiology of some cases of hSLE.
Yamaguchi
Hiroshi
H
Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto 606-8501, Japan.
Takagi
Junichi
J
Miyamae
Takako
T
Yokota
Shumpei
S
Fujimoto
Takashi
T
Nakamura
Shinobu
S
Ohshima
Shiro
S
Naka
Tetsuji
T
Nagata
Shigekazu
S
D016475:3T3 Cells; D000328:Adult; D000818:Animals; D000954:Antigens, Surface / Q000097:blood* / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D002648:Child; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008894:Milk Proteins / Q000097:blood* / Q000235:genetics*; D010587:Phagocytosis; D010743:Phospholipids / Q000097:blood; D011994:Recombinant Proteins / Q000378:metabolism; D020298:U937 Cells
D000954:Antigens, Surface; D015415:Biomarkers; C098942:MFGE8 protein, human; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D010743:Phospholipids; D011994:Recombinant Proteins