The role of endogenous antibiotics, Cathelicidin in liver regeneration

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The mechanism of host defense of Vertebrates consists of both acquired and innate immune systems. The former is the specific system of Vertebrates. The recognition of pathogens by immunoglobulin or T cell receptor is specific. On the other hand the later exists universally in the lower animals such as insect. It has the important role for the host defense with the front line of pathogens. Cathelicidins are mammalian endogenous antibiotic, which works as the effecter molecule of innate immunity, induces the synthesis of a transmembrane heparin sulphate proteoglycan involved in co-factor of epidermal growth factor receptor (EGFR) in skin wound healing. Previously we revealed that the importance of the host defense in skin infection model (Nature,2001) and the lack of the expression of cathelicidin is the cause of secondary infection in atopic dermatitis (N Engl J Med,2002). Furthermore, porcine cathelicidin, PR-39 induce angiogenesis in model of rat myocardial infarction. Existence of ca … More thelicidin in macrophage, and stimuli by lipopolysacchaloid (LPS) induce the expression of cathelicidin via Toll like receptor (TLR). Recently the importance of Kupffer cells in liver regeneration is reported. We hypotheses that cathelicidin in Kupffer cell could induce proliferation of hepatocytes directly and indirectly. Actually we revealed that the expression of mRNA of TLR-3 to 8 and 10 in normal liver tissue by RTPCR. However we could reveal that the signals of expression of cathelicidin in recruiting neutrophils but not Kupffer cells in normal liver tissue. Therefore for investigation and evaluation of bactericidal activity and tissue healing activity, we used mouse skin infection model and generated two cathelicidin transgenic mice.Cathelicidin antimicrobial peptides are effectors of innate immune defense in mammals. Humans and mice have only one cathelicidin gene, whereas domesticated mammals such as the pig, cow, and horse have multiple cathelicidin genes. We hypothesized that the evolution of multiple cathelicidin genes provides these animals with enhanced resistance to infection. To test this, we investigated the effects of the addition of cathelicidins by combining synthetic cathelicidin peptides in vitro, by producing human keratinocytes that overexpress cathelicidins in culture, or by producing transgenic mice that constitutively overexpress cathelicidins in vivo. The porcine cathelicidin peptide PR-39 acted additively with human cathelicidin LL-37 to kill group A Streptococcus (GAS). Lentiviral delivery of PR-39 enhanced killing of GAS by human keratinocytes. Finally, transgenic mice expressing PR-39 under the influence of a K14 promoter showed increased resistance to GAS skin infection (50% smaller necrotic ulcers and 60% fewer surviving bacteria). Similarly constructed transgenic mice designed to overexpress their native cathelicidin did not show increased resistance. These findings demonstrate that targeted gene transfer of a xenobiotic cathelicidin confers resistance against infection and suggests the benefit of duplication and divergence in the evolution of antimicrobial peptides. Less