ABSTRACT: To explore the possibility that bone morphogenetic proteins (BMPs) are autocrine/paracrine regulators of hematopoietic differentiation and function, we screened a panel of human cell lines encompassing the hematopoietic lineages for expression of members of this family of genes. Expression of BMP-2, BMP-4, BMP-6, BMP-7, Growth and Differentiation Factor-1 (GDF-1), Placental Bone Morphogenetic Protein (PLAB), and Transforming Growth Factor-beta3 (TGF-beta3) was detected in one or more cell lines. BMP-2, BMP-4, BMP-7, and TGF-beta3 expression was also found in normal hematopoietic tissue. Expression of BMP-5 and BMP-8 was not seen. Lineage-restricted patterns of expression were found for BMP-4 (T-lymphoid), BMP-7 (lymphoid), PLAB (macrophage/monocyte), and GDF-1 (myeloid). Expression of BMP-2, GDF-1, and PLAB could be modulated by treatment with differentiating agents. Marked variations in the levels of BMP-4, BMP-7, and PLAB expression were encountered, indicating that disorders in BMP signaling path ways may play a role in the development of hematopoietic neoplasia.

Keywords: Bone morphogenetic proteins, lineage-restricted expression, hematopoiesis, differentiation, hematopoietic cell lines, neoplasia.

Reprint requests to: Kristina Detmer, Ph.D., Division of Basic Medical Sciences, Mercer University School of Medicine, 1550 College St., Macon, GA 31207, fax: (912) 301-5489, e-mail: detmer.k@gain.mercer.edu.

ABSTRACT: We analyzed the frequency of the C282Y and H63D mutations in the HFE gene in 227 individuals from Brazil comprising 71 Caucasians, 91 racially mixed Caucasian African-derived Amerindians (both populations from Southeast Brazil), 85 African-derived subjects (from Northeast Brazil) and 75 Parakan Indians. Allelic frequency of the mutation C. 845G6A (C282Y) was 1.4% in the Caucasian population, 1.1% in the African-derived population, 1.1% in the racially mixed normal controls and 0% in the Parakan Indians. In the African-derived population, the C282Y mutation was present on chromosomes bearing the haplotype 6/1h according to Beutler and West (1997). Allelic frequency of the mutation C. 187C6G (H63D) was 16.3% in the Caucasian population, 7.5% in the African-derived population, 9.8% in the racially mixed controls and 0% in the Amerindians. The presence of these mutations in the African-derived population reflects the fact that these subjects may have undergone a non-identified racial admixture in their past history. The absence of both defects in the Amerindians suggests that these mutations have emerged after the migration of Polynesians to America, or that they may not have reached the Polynesian population until after the migration to America had occurred.

Keywords: Hemochromatosis, HFE gene, Brazilian population, Amerindians, Parakan Indians.

Reprint requests to: Sara T.O. Saad, Hemocentro UNICAMP, CP6198, Campinas, SP, Brazil, CEP 13083-970, fax: +55 19 289-1089, e-mail: sara@obelix.unicamp.br.

ABSTRACT: In mouse macrophages (RAW 264.7 cells), toll-like receptor 4 (Tlr4) is a limiting factor in lipopolysaccharide (LPS) signal transduction. The expression of only 1-2 x 10^4 copies of recombinant Tlr4 per cell enhances sensitivity to LPS, shifting the EC50 by 30-fold to the left. Expression of the Tlr4^Lps-d isoform of Tlr4 (found in C3H/HeJ mice) shifts the EC50 2600-fold to the right, essentially abolishing LPS responses. A truncated form of Tlr4, lacking a cytoplasmic domain, exerts only a weak inhibitory effect on signal transduction. Similarly, the normal or Tlr4^Lps-d forms of protein lacking a cytoplasmic domain, cause modest inhibition of LPS signaling. Manipulations of Tlr4 structure and expression cause changes in LPS sensitivity that range over 3 to 4 orders of magnitude. These findings support the view that Tlr4 is an integral component of a solitary pathway for LPS signal transduction in macrophages and permit inferences related to the mechanism of signaling and its blockade.

Keywords: Toll-like receptor 4, macrophage, endotoxin, receptor, mutagenesis.

Reprint requests to: Dr. Bruce Beutler, Howard Hughes Medical Institute, 5323 Harry Hines Blvd., Y5.224, Dallas TX 75235-9050, fax: (214) 648-6395, e-mail: beutler@howie.swmed.edu.