Mohamed Zaiou

An angiogenic role for the human peptide antibiotic LL-37/hCAP-18

Antimicrobial peptides are effector molecules of the innate immune system and contribute to host defense and regulation of inflammation. The human cathelicidin antimicrobial peptide LL-37/hCAP-18 is expressed in leukocytes and epithelial cells and secreted into wound and airway surface fluid. Here we show that LL-37 induces angiogenesis mediated by formyl peptide receptor-like 1 expressed on endothelial cells. Application of LL-37 resulted in neovascularization in the chorioallantoic membrane assay and in a rabbit model of hind-limb ischemia. The peptide directly activates endothelial cells, resulting in increased proliferation and formation of vessel-like structures in cultivated endothelial cells. Decreased vascularization during wound repair in mice deficient for CRAMP, the murine homologue of LL-37/hCAP-18, shows that cathelicidin-mediated angiogenesis is important for cutaneous wound neovascularization in vivo. Taken together, these findings demonstrate that LL-37/hCAP-18 is a multifunctional antimicrobial peptide with a central role in innate immunity by linking host defense and inflammation with angiogenesis and arteriogenesis.

Cathelicidins, essential gene-encoded mammalian antibiotics

Abstract. Cathelicidins are a class of gene-encoded antibiotics found exclusively in mammals. In vitro and in vivo studies indicate they are effector molecules of mammalian innate immunity that can provide a first line of defense against an array of micro-organisms. Additional functions are described for some members of this class of antimicrobial peptides including chemotactic activity, mitogenesis, and angiogenesis. Therefore these peptides are considered to be multifunctional effector molecules. This review discusses recent progress in cathelicidin research and the functional properties of cathelicidins. Current work in this field suggests that understanding this component of the mammalian innate immune system and related natural antibiotic peptides offer an opportunity for the development of novel therapeutic agents with which to battle the continued problem of antimicrobial resistance.

Multifunctional antimicrobial peptides: therapeutic targets in several human diseases

Antimicrobial peptides have emerged as promising agents against antibiotic-resistant pathogens. They represent essential components of the innate immunity and permit humans to resist infection by microbes. These gene-encoded peptides are found mainly in phagocytes and epithelial cells, showing a direct activity against a wide range of microorganisms. Their role has now broadened from that of simply endogenous antibiotics to multifunctional mediators, and their antimicrobial activity is probably not the only primary function. Although antimicrobial peptide deficiency, dysregulation, or overproduction is not known to be a direct cause of any single human disease, numerous studies have now provided compelling evidence for their involvement in the complex network of immune responses and inflammatory diseases, thereby influencing diverse processes including cytokine release, chemotaxis, angiogenesis, wound repair, and adaptive immune induction. The purpose of this review is to highlight recent literature, showing that antimicrobial peptides are associated with several human conditions including infectious and inflammatory diseases, and to discuss current clinical development of peptide-based therapeutics for future use.

Keratinocyte Production of Cathelicidin Provides Direct Activity against Bacterial Skin Pathogens

ABSTRACT Immune defense at an interface with the external environment reflects the functions of physical and chemical barriers provided by epithelial and immune cells. Resident epithelial cells, such as keratinocytes, produce numerous peptides with direct antimicrobial activity but also provide a physical barrier against invading pathogens and signal the recruitment of circulating immune cells, such as neutrophils. Antimicrobial peptides such as cathelicidin are produced constitutively by neutrophils and are inducible in keratinocytes in response to infection. The multiplicity of antimicrobial peptides and their cellular sources has resulted in an incomplete understanding of the role of cathelicidin production by epithelial cells in cutaneous immune defense. Therefore, this study sought to evaluate keratinocyte antimicrobial activity and the potential contribution of keratinocyte cathelicidin to host protection against two leading human skin pathogens. Wild-type mice and those with a targeted deletion of the cathelicidin gene, Cnlp, were rendered neutropenic prior to cutaneous infection. Interestingly, Cnlp-deficient mice remained more susceptible to group A streptococcus infection than mice with Cnlp intact, suggesting the involvement of epithelial cell-derived cathelicidin in host immune defense. Keratinocytes were then isolated in culture and found to inhibit the growth of Staphylococcus aureus, an effect that was partially dependent on their ability to synthesize and activate cathelicidin. Further, lentivirus-mediated delivery of activated human cathelicidin enhanced keratinocyte antimicrobial activity. Combined, these data illustrate the potential contribution of keratinocyte cathelicidin to the innate immune defense of skin against bacterial pathogens and highlight the need to consider epithelial antimicrobial function in the diagnosis and therapy of skin infection.

IL-6, TNF-α and atherosclerosis risk indicators in a healthy family population: the STANISLAS cohort

There are no satisfactory data on circulating concentrations of inflammatory cytokines and their potential relationship with traditional and nontraditional atherosclerosis risk factors in a large healthy young population. The present study was conducted to examine, in 179 healthy families selected from the STANISLAS cohort, the association between interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP), orosomucoid, haptoglobin, cell-adhesion molecules (ICAM-1, E-, L- and P-selectin) and lipid parameter concentrations. Age, BMI, white blood cells and tobacco consumption contributed to the variation of IL-6 concentrations. Age and tobacco contributed also to TNF-alpha variation. Taking into account potential covariates, we showed strong positive correlation between IL-6 and both inflammatory markers TNF-alpha and CRP in parents and in offspring (P<0.001). In parents, IL-6 was associated with ICAM-1 and L-selectin (P<0.01), while IL-6 and TNF-alpha predicted E-selectin in offspring only (0.001<P<0.01). Furthermore, IL-6 showed a strong negative relationship with apo A-1 and HDL-cholesterol in females only (P<0.001). This study demonstrated that in a large healthy family population, children included, levels of IL-6 are closely associated with traditional and non-traditional atherosclerosis risk factors. All these data are useful for defining the precise role of cytokines in atherosclerosis mechanisms in physiological conditions.

Genetic determinants of blood pressure regulation.

Hypertension is a multifactorial disorder that probably results from the inheritance of a number of susceptibility genes and involves multiple environmental determinants. Existing evidence suggests that the genetic contribution to blood pressure variation is about 30–50%. Although a number of candidate genes have been studied in different ethnic populations, results from genetic analysis are still inconsistent and specific causes of hypertension remain unclear. Furthermore, the abundance of data in the literature makes it difficult to piece together the puzzle of hypertension and to define candidate genes involved in the dynamic of blood pressure regulation. In this review, we attempt to highlight the genetic basis of hypertension pathogenesis, focusing on the most important existing genetic variations of candidate genes and their potential role in the development of this disease. Our objective is to review current knowledge and discuss limitations to clinical applications of genotypic information in the diagnosis, evaluation and treatment of hypertension. Finally, some principles of pharmacogenomics are presented here along with future perspectives of hypertension.

Human formyl peptide receptor 1 (FPR1) c.32C>T SNP is associated with decreased soluble E-selectin levels.

AIMS The human formyl peptide receptor (FPR) is a G protein-coupled chemoattractant receptor that is thought to mediate inflammatory responses. The FPR1 gene is highly polymorphic. In a recent study, the FPR1 c.32C>T SNP, resulting in the amino-acid substitution I11T, was reported to be significantly associated with C-reactive protein levels. Therefore, this study sought to determine if the impact of such a genetic variation extends to other clinical parameters associated with inflammation, including cytokines, adhesion molecules and inflammatory markers. MATERIALS & METHODS This study was carried out on a subsample of 325 adults selected from the STANISLAS cohort study. The FPR1 c.32C>T SNP was genotyped using PCR amplification followed by restriction enzyme digestion. Anthropometric measurements and biochemical profiles were assessed for each individual. RESULTS The allele frequencies of FPR1 c.32C>T were 0.74 for the 32C allele and 0.26 for the 32T allele. Genotype frequencies were 0.55 for C/C, 0.38 for C/T and 0.07 for T/T. After adjusting for age, sex, BMI, alcohol and cigarette consumption, oral contraceptive, antibiotics and anti-inflammatory drug use, statistical analysis (under a recessive model of inheritance) demonstrated that serum E-selectin levels were 68% lower in individuals homozygous for T/T than in those with C/T or C/C genotypes (p = 0.001). However, no significant correlations were found for C-reactive protein or the other 18 tested clinical parameters that were analyzed in this study. CONCLUSION The FPR1 c.32C>T SNP may be associated with E-selectin levels in the French population. Although of importance, these findings need confirmation in larger studies.