ABSTRACT
Using a cDNA microarray from Incyte Genomics, we performed gene expression profi ling in lungs from mice treated with hypoxia (10%, normal baric) for 4 d. Data analysis showed that there are 270 genes and expressed sequence tags (ESTs) signifi cantly upregulated out of 9,415 gene elements. Th e highest upregulated ESTs with Genbank accession number AA712003 are increased more than 4-fold in the hypoxic lung compared with the normoxic controls. Further studies showed that AA712003 has identical sequence to FIZZ1 and RELMα. We named this homologue hypoxia-induced mitogenic factor (HIMF) because of its potent mitogenic action on PMVSMC and its upregulation by hypoxia. HIMF belongs to the resistin protein families (Holcomb et al. 2000), whose members encode proteins of 105-114 amino acids with three domains: (1) an N-terminal signal sequence, (2) a variable middle portion, and (3) a highly conserved C-terminal signature sequence that constitutes nearly half of the molecule. Th e signature region of HIMF contains a unique and invariant spacing of the cysteine residues: C-X11-C-X8-C-X-C-X3-C-X10-C-X-C-X-C-X9-CC-X3-6-END (C represents cycteine and X is any amino acid residue). Th is is reminiscent of the so-called “EGF repeats” that are characteristic of a number of signaling molecules. Most important, studies from our laboratory have shown that HIMF enhances VCAM-1 gene production in MLE-12 and endothelial cells. In LPS-treated cells and lung, HIMF is highly upregulated accompanied by increased monocyte sequestration in the lung parenchyma and levels of VCAM-1 expression. Administration of recombinant HIMF into the lung induced robust upregulation of VCAM-1. Th ese fi ndings strongly indicate that HIMF may be an important cytokine-like protein participating in the infl ammatory process via modulation of adhesion molecule expression in the lung.
