| The ontogeny and function of hematopoietic system concerns numerous proteins produced by hematopioetic cells. In this study, we explored the function and clinical significance of two of the proteins, LL-37/hCAP-18 and EDAG.Antimicrobial peptide LL-37/hCAP-18 that is mainly produced by neutrophils, is important in host innate-immune defense. LL-37/hCAP-18 is synthesized as a pre-pro-peptide with 19.3 kD including a signal peptide, a cathelin-Iike domain and a 37-residue antimicrobial domain. The pro-peptide is 18 kD and is designated as hCAP-18. Cleavage of hCAP-18 by proteinase 3 liberates its C-terminal, active biologic domain (LL-37) from the conserved cathelin-Iike prosequence. LL-37 exhibits potent antimicrobial activity against Gram-negative and Gram-positive bacteria. It also has the ability to bind and neutralize the biological activity of lipopolysaccharide (LPS). Its deficiency may increase the susceptibility to infection. Involvement of LL-37 in pathological processes has been reported in many diseases. However, the knowledge of the expression of LL-37/hCAP-18 in hematological diseases and its clinical relevance is limited.We detected LL-37/hCAP-18 expression in the peripheral blood smears of 50 healthy donors and 143 patients with various hematological diseases. Compared with that in the healthy donors, expression of the protein in the neutrophils was significantly lower in patients with AML(93.8±3.5% versus 26.6±12.8%, p<0.05), especially those with infection. LL-37/hCAP-18 has been shown to play a role in host defense, and its deficiency in AML may be one of the explanations for their susceptibilities to infection among these patients. However, no significant difference was detected on the mRNA level between the neutrophils of the healthy donors and the AML patients suggesting that post-transcriptional mechanisms govern the expression of LL-37/hCAP-18 protein. Since 5'-UTR contains elements which are important in the regulation of translation, we detected the 5'-UTR sequences of LL-37/hCAP-18 gene in Raji, NB4, HL-60, J6-1 and U937 cells. There was no abnormality in the 5'-UTR sequences in these leukemia cell lines.Recently, other effects of LL-37 related to immune response have been gradually unveiled. LL-37 is chemotactic for human monocytes, neutrophils and T lymphocytes and acts as a potent modifier of DC differentiation. It was reported that defensin, another multifunctional antimicrobial peptide with chemotactic responses, could enhance the immunogenicity of the tumor antigen or viral antigen when fused with these antigens in DNA vaccination. Whether LL-37 has similar effects in antitumor immunity remains unclear. Previously, our lab constructed an M-CSFR DNA vaccine, which could induce humoral and cellular immunity against M-CSFR bearing SP2/0 cells in a murine model and markedly prolong the survival of mice challenged with M-CSFR+ tumor. In this study, we also used this model with necessary modification and investigated whether LL-37 could enhance the antitumor activities of the vaccines against M-CSFR by altering the... |
