J. Schröder - Academia.edu (original) (raw)

Papers by J. Schröder

Journal of Pediatric Gastroenterology and Nutrition, 2004

PLoS ONE, 2013

Chemerin, a chemoattractant ligand for chemokine-like receptor 1 (CMKLR1) is predicted to share s... more Chemerin, a chemoattractant ligand for chemokine-like receptor 1 (CMKLR1) is predicted to share similar tertiary structure with antibacterial cathelicidins. Recombinant chemerin has antimicrobial activity. Here we show that endogenous chemerin is abundant in human epidermis, and that inhibition of bacteria growth by exudates from organ cultures of primary human skin keratinocytes is largely chemerin-dependent. Using a panel of overlapping chemerin-derived synthetic peptides, we demonstrate that the antibacterial activity of chemerin is primarily mediated by Val 66-Pro 85 , which causes direct bacterial lysis. Therefore, chemerin is an antimicrobial agent in human skin.

Journal of Allergy and Clinical Immunology, 2000

There is substantial scientific and clinical evidence that allergic rhinitis frequently coexists ... more There is substantial scientific and clinical evidence that allergic rhinitis frequently coexists with asthma. and sinusitis and may be a predisposing factor for both. In addition, a number of studies have demonstrated that nasal inflammation and obstruction,

Inflammatory Bowel Diseases, 2003

Antimicrobial peptides such as defensins provide nonspecific mucosal defense against a multitude ... more Antimicrobial peptides such as defensins provide nonspecific mucosal defense against a multitude of microorganisms. Recently, it has been shown that luminal bacteria may invade the mucosa in inflammatory bowel diseases, suggesting a defect in innate mucosal immunity. The aim of this study was to investigate the expression of human ␤-defensins (HBD) in controls, Crohn's disease (CD), ulcerative colitis (UC), and unspecific inflammation. Up to 4 biopsies were taken from 103 patients (33 controls, 24 with Crohn's disease, 36 with ulcerative colitis, 10 with unspecific colitis). Mucosal mRNA was measured using real-time fluorescence temperature cycler reverse-transcription polymerase chain reaction with primers for HBD-1, HBD-2, HBD-3, tumor necrosis factor ␣, and interleu-kin 8. Mucosal HBD-1 expression was marginally decreased in both CD and UC. HBD-2 was increased exclusively in UC but not in CD. The expression of the novel defensin HBD-3 was strongly correlated with HBD-2 and also raised predominantly in UC. The expression of both inducible ␤-defensins was enhanced in the state of inflammation. Expression of HBD-2 showed a weak correlation with interleukin 8 only in inflamed CD biopsies but not with tumor necrosis factor ␣. The missing induction of both inducible ␤-defensins in CD as compared with UC may cause a defect in barrier function that predisposes to bacterial invasion.

Gastroenterology, 2001

IL-ltg-induced IK8 degradation/phosphory~ation and ReJA nuclear translocation was blocked in Ad5d... more IL-ltg-induced IK8 degradation/phosphory~ation and ReJA nuclear translocation was blocked in Ad5dnAKT-infected IEC-6 cells. Surprisingly, IL-6 and ICAM-1 gene expression was higher in LPS-stimulated, Ad5dnAKT-infectad cells than with LPS alone. Ad5dnTAK1 blocked iKBo~legradation and RelA nuclear translocation in TNF-stimulated, but only transiently inhibited ILl B-mediated RelA translocation (<10min) in Ad5dnTAKl-infected iEC-6 cells. This suggests redundancy of TAK1 in IL-16 sionalin0. LPS and TNF-induced IL-8 secretion was partially inhibited in Ad5dnTAKl-infected HT-29 cells by 49 and 53% respectively. Conduslon: These data demonstrate for the first time that TAK1 and AK'I" are part of LPS signal transduction to NF-KB. Interestingly, AKT provides a negative feedback for LPS signaling to ICAM-1 and IL-6 gone expression. The role of AKT might be NF-KB independent and may serve to keep LPS signaling in check. Therefore, blockade of TAK1 or AKT would have a differential impact on IEC gene expression depending on the source of cell surface stimulation.

Antimicrobial peptides represent the rst-line host defence against microbial pathogens and an ess... more Antimicrobial peptides represent the rst-line host defence against microbial pathogens and an essential component of innate immunity. They have received growing interest because of their potential use as therapeutic antibiotics. Due to the fact that most antimicrobial peptides are toxic to prokaryotic host cells, they are currently often produced by chemical synthesis. However, this is too costly for them to be used when large quantities of antimicrobial peptides are required for investigations and clinical trials. Thus, the convenience and cost e ciencies of bacterial production of antimicrobial peptides have become a bottleneck problem. As an important group of antimicrobial peptides human ß-defensins are cationic peptides with 38-47 amino acid residues showing three strands of anti-parallel β-sheets that provide a compact small structure \[1,2]. We describe an optimized strategy for recombinant expression of hBD-1 and its mutants in _Escherichia coli_, to e ciently produce milligram quantities of pure oxidized and correctly folded hBD-1, which was converted into its fully reduced form in a previous study \[3]. Recombinant hBD-1 and its mutants were used in its linearized form for bactericidal testing, nuclear magnetic resonance spectroscopy as well as generation of speci c polyclonal antibodies. Here we present a step-by-step protocol, with minor modi cations, which might be applied also for production of other cysteine-rich and linearized antimicrobial peptides in _E.coli_ and their speci c polyclonal antibodies.

Science, 1999

References and Notes 1. A. Kumar, HA Biebuyck, NL Abbott, GM White- sides, J. Am. Chem. Soc. 114,... more References and Notes 1. A. Kumar, HA Biebuyck, NL Abbott, GM White- sides, J. Am. Chem. Soc. 114, 9188 (1992). 2. DW Wang, SG Thomas, KL Wang, Y. Xia, GM Whitesides, Appl. Phys. Lett. 70, 1593 (1997). 3. RJ Jackman, JL Wilbur, GM ...

Die Erfindung betrifft Proteine, die antibiotisch wirksam sind. Es handelt sich um SAP-2 und SAP-... more Die Erfindung betrifft Proteine, die antibiotisch wirksam sind. Es handelt sich um SAP-2 und SAP-3. Weiterhin umfasst die Erfindung ein Verfahren zur Reinigung von bestimmten antimikrobiellen Proteinen. Daruber hinaus bezieht sich die Erfindung auf eine Verwendung der antimikrobiellen Proteine zur antibiotischen Behandlung oder auf eine Verwendung von Zellen, welche mit einer DNA transfiziert wurden, die fur die erfindungsgemassen Proteine kodiert.

Proceedings of the National Academy of Sciences, 2015

Significance Fungi increasingly cause serious medical problems in immunocompromised populations. ... more Significance Fungi increasingly cause serious medical problems in immunocompromised populations. Antimicrobial peptides are primary effector molecules of innate immune systems. Antimicrobial peptides successfully protect healthy humans from bacterial infections. However, it is largely unknown how and why human body surfaces resist fungal infections. We identified the common epithelial protein, psoriasin (S100A7), in its disulphide-reduced form (redS100A7) as the principal antifungal factor of human body surfaces. redS100A7 kills several pathogenic fungi using a mechanism that differs from conventional antifungal agents. Thus, this study might contribute to a better understanding of human defense systems against fungal infection and the development of urgently needed novel antifungal therapeutics.

PLoS ONE, 2013

Chemerin, a chemoattractant ligand for chemokine-like receptor 1 (CMKLR1) is predicted to share s... more Chemerin, a chemoattractant ligand for chemokine-like receptor 1 (CMKLR1) is predicted to share similar tertiary structure with antibacterial cathelicidins. Recombinant chemerin has antimicrobial activity. Here we show that endogenous chemerin is abundant in human epidermis, and that inhibition of bacteria growth by exudates from organ cultures of primary human skin keratinocytes is largely chemerin-dependent. Using a panel of overlapping chemerin-derived synthetic peptides, we demonstrate that the antibacterial activity of chemerin is primarily mediated by Val 66-Pro 85 , which causes direct bacterial lysis. Therefore, chemerin is an antimicrobial agent in human skin.

Experimental Dermatology, 2006

Journal of Investigative Dermatology, 2008

Human epidermis elaborates two small cationic, highly hydrophobic antimicrobial peptides (AMP), b... more Human epidermis elaborates two small cationic, highly hydrophobic antimicrobial peptides (AMP), beta-defensin 2 (hBD2), and the carboxypeptide cleavage product of human cathelicidin (hCAP18), LL-37, which are co-packaged along with lipids within epidermal lamellar bodies (LBs) before their secretion. Because of their colocalization, we hypothesized that AMP and barrier lipid production could be coregulated by altered permeability barrier requirements. mRNA and immunostainable protein levels for mBD3 and cathelin-related antimicrobial peptide (CRAMP) (murine homologues of hBD2 and LL-37, respectively) increase 1-8 hours after acute permeability barrier disruption and normalize by 24 hours, kinetics that mirror the lipid metabolic response to permeability barrier disruption. Artificial permeability barrier restoration, which inhibits the lipid-synthetic response leading to barrier recovery, blocks the increase in AMP mRNA/protein expression, further evidence that AMP expression is linked to permeability barrier function. Conversely, LB-derived AMPs are also important for permeability barrier homeostasis. Despite an apparent increase in mBD3 protein, CRAMP-/- mice delayed permeability barrier recovery, attributable to defective LB contents and abnormalities in the structure of the lamellar membranes that regulate permeability barrier function. These studies demonstrate that (1) the permeability and antimicrobial barriers are coordinately regulated by permeability barrier requirements and (2) CRAMP is required for permeability barrier homeostasis.

Nature, Jan 26, 1997

... Biochem. Biophys. Res. Comm. 225, 1045–1051 (1996). NATURE | VOL 387 | 26 JUNE 1997 861 A pep... more ... Biochem. Biophys. Res. Comm. 225, 1045–1051 (1996). NATURE | VOL 387 | 26 JUNE 1997 861 A peptide antibiotic from human skin scientific correspondence ...

Nature Immunology, 2005

Human healthy skin is continuously exposed to bacteria, but is particularly resistant to the comm... more Human healthy skin is continuously exposed to bacteria, but is particularly resistant to the common gut bacterium Escherichia coli. We show here that keratinocytes secrete, as the main E. coli-killing compound, the S100 protein psoriasin in vitro and in vivo in a site-dependent way. In vivo treatment of human skin with antibodies to psoriasin inhibited its E. coli-killing properties. Psoriasin was induced in keratinocytes in vitro and in vivo by E. coli, indicating that its focal expression in skin may derive from local microbial induction. Zn(2+)-saturated psoriasin showed diminished antimicrobial activity, suggesting that Zn(2+) sequestration could be a possible antimicrobial mechanism. Thus, psoriasin may be key to the resistance of skin against E. coli.

Journal of Investigative Dermatology, 1992

Neutrophil accumulation in the epidermis is a histologic characteristic of psoriasis. We addresse... more Neutrophil accumulation in the epidermis is a histologic characteristic of psoriasis. We addressed the question: What is the major protein-like chemotactic principle responsible for neutrophil accumulation? Purification of proteinaceous neutrophil chemoattractants from extracts obtained from psoriatic scales by multistep high-performance liquid chromatography (HPLC) yielded three biochemically distinct polypeptides with potent neutrophil chemotactic activity. Aminoterminal amino acid sequence analysis of the quantitatively major neutrophil attractant revealed the sequence ELRXQXIKTYSK, which is identical to that of a 69 residue form of neutrophil-activating peptide-1/interleukin 8 (NAP-1/IL-8). The second major attractant showed the sequence XXVATELRXQXL . . ., which is identical to that of the gene product of the oncogene &quot;gro&quot; as well as &quot;melanoma growth stimulatory activity, MGSA,&quot; whereas the third and minor neutrophil chemotaxin has an NH2-terminal sequence identical with NAP-1/IL-8. Estimation of NAP-1/IL-8-related proteins and gro/MGSA by HPLC combined with bioassay revealed a mean of 3.3 +/- 1.7 ng NAP-1/IL-8-related proteins (n = 11) and 3.2 +/- 1.9 ng gro/MGSA (n = 11) per 1 mg psoriatic scales. In normal heel callus (n = 8), these neutrophil attractants were found at concentrations below 0.02 +/- 0.01 ng/mg. The finding of more than 150-times increased amounts of both NAP-1/IL-8 and gro/MGSA in lesional psoriasis material suggest that these mitogenic as well as neutrophil- and lymphocyte-chemotactic compounds may play an important role in the pathogenesis of psoriasis.

Journal of Investigative Dermatology, 1991

Neutrophil-activating protein-1/interleukin 8 (NAP-1/IL-8), purified to homogeneity from lipopoly... more Neutrophil-activating protein-1/interleukin 8 (NAP-1/IL-8), purified to homogeneity from lipopolysaccharide-stimulated human peripheral blood monocytes, was injected intracutaneously into human skin. Sequential biopsy specimens were taken in order to investigate the sequence of ultrastructural changes induced by the cytokine. Whereas intracutaneous injection of 100 ng of NAP-1/IL-8 per site caused no macroscopic changes, by histology infiltration with polymorphonuclear leukocytes (PMN) and monocytes was present within 1 h and increased at 3 and 5 h. No lymphocyte infiltration was noted. The first ultrastructural changes (30 min) consisted of the presence of cytoplasmic 7-nm microfilament bundles, as well as numerous protrusions of the luminal plasma membrane of endothelial cells (EC). As a striking feature, multiple 100- to 160-nm electron lucent vesicles could be observed in the EC cytoplasm. These structures differed from plasmalemmal vesicles and suggest secretory activity. When PMN and monocytes appeared in the vascular lumen (1 h and later), the number of 100-160-nm electron-lucent vesicles had decreased significantly. In contrast to C5a-injected skin sites, mast cell degranulation was absent.

Journal of Investigative Dermatology, 1996

Epidermal infiltration by polymorphonuclear cells is a prominent feature in psoriatic lesions. Ex... more Epidermal infiltration by polymorphonuclear cells is a prominent feature in psoriatic lesions. Expression of neutrophil-specific chemoattractants by lesional keratinocytes could play an important role in the regulation of this infiltration process. We therefore examined the mRNA expression of GRO-α, a well-characterized peptide with neutrophil-specific activation profile in psoriatic lesions by in situ hybridization. Clusters of clearly detectable and in some

Journal of Pediatric Gastroenterology and Nutrition, 2004

PLoS ONE, 2013

Chemerin, a chemoattractant ligand for chemokine-like receptor 1 (CMKLR1) is predicted to share s... more Chemerin, a chemoattractant ligand for chemokine-like receptor 1 (CMKLR1) is predicted to share similar tertiary structure with antibacterial cathelicidins. Recombinant chemerin has antimicrobial activity. Here we show that endogenous chemerin is abundant in human epidermis, and that inhibition of bacteria growth by exudates from organ cultures of primary human skin keratinocytes is largely chemerin-dependent. Using a panel of overlapping chemerin-derived synthetic peptides, we demonstrate that the antibacterial activity of chemerin is primarily mediated by Val 66-Pro 85 , which causes direct bacterial lysis. Therefore, chemerin is an antimicrobial agent in human skin.

Journal of Allergy and Clinical Immunology, 2000

There is substantial scientific and clinical evidence that allergic rhinitis frequently coexists ... more There is substantial scientific and clinical evidence that allergic rhinitis frequently coexists with asthma. and sinusitis and may be a predisposing factor for both. In addition, a number of studies have demonstrated that nasal inflammation and obstruction,

Inflammatory Bowel Diseases, 2003

Antimicrobial peptides such as defensins provide nonspecific mucosal defense against a multitude ... more Antimicrobial peptides such as defensins provide nonspecific mucosal defense against a multitude of microorganisms. Recently, it has been shown that luminal bacteria may invade the mucosa in inflammatory bowel diseases, suggesting a defect in innate mucosal immunity. The aim of this study was to investigate the expression of human ␤-defensins (HBD) in controls, Crohn's disease (CD), ulcerative colitis (UC), and unspecific inflammation. Up to 4 biopsies were taken from 103 patients (33 controls, 24 with Crohn's disease, 36 with ulcerative colitis, 10 with unspecific colitis). Mucosal mRNA was measured using real-time fluorescence temperature cycler reverse-transcription polymerase chain reaction with primers for HBD-1, HBD-2, HBD-3, tumor necrosis factor ␣, and interleu-kin 8. Mucosal HBD-1 expression was marginally decreased in both CD and UC. HBD-2 was increased exclusively in UC but not in CD. The expression of the novel defensin HBD-3 was strongly correlated with HBD-2 and also raised predominantly in UC. The expression of both inducible ␤-defensins was enhanced in the state of inflammation. Expression of HBD-2 showed a weak correlation with interleukin 8 only in inflamed CD biopsies but not with tumor necrosis factor ␣. The missing induction of both inducible ␤-defensins in CD as compared with UC may cause a defect in barrier function that predisposes to bacterial invasion.

Gastroenterology, 2001

IL-ltg-induced IK8 degradation/phosphory~ation and ReJA nuclear translocation was blocked in Ad5d... more IL-ltg-induced IK8 degradation/phosphory~ation and ReJA nuclear translocation was blocked in Ad5dnAKT-infected IEC-6 cells. Surprisingly, IL-6 and ICAM-1 gene expression was higher in LPS-stimulated, Ad5dnAKT-infectad cells than with LPS alone. Ad5dnTAK1 blocked iKBo~legradation and RelA nuclear translocation in TNF-stimulated, but only transiently inhibited ILl B-mediated RelA translocation (<10min) in Ad5dnTAKl-infected iEC-6 cells. This suggests redundancy of TAK1 in IL-16 sionalin0. LPS and TNF-induced IL-8 secretion was partially inhibited in Ad5dnTAKl-infected HT-29 cells by 49 and 53% respectively. Conduslon: These data demonstrate for the first time that TAK1 and AK'I" are part of LPS signal transduction to NF-KB. Interestingly, AKT provides a negative feedback for LPS signaling to ICAM-1 and IL-6 gone expression. The role of AKT might be NF-KB independent and may serve to keep LPS signaling in check. Therefore, blockade of TAK1 or AKT would have a differential impact on IEC gene expression depending on the source of cell surface stimulation.

Antimicrobial peptides represent the rst-line host defence against microbial pathogens and an ess... more Antimicrobial peptides represent the rst-line host defence against microbial pathogens and an essential component of innate immunity. They have received growing interest because of their potential use as therapeutic antibiotics. Due to the fact that most antimicrobial peptides are toxic to prokaryotic host cells, they are currently often produced by chemical synthesis. However, this is too costly for them to be used when large quantities of antimicrobial peptides are required for investigations and clinical trials. Thus, the convenience and cost e ciencies of bacterial production of antimicrobial peptides have become a bottleneck problem. As an important group of antimicrobial peptides human ß-defensins are cationic peptides with 38-47 amino acid residues showing three strands of anti-parallel β-sheets that provide a compact small structure \[1,2]. We describe an optimized strategy for recombinant expression of hBD-1 and its mutants in _Escherichia coli_, to e ciently produce milligram quantities of pure oxidized and correctly folded hBD-1, which was converted into its fully reduced form in a previous study \[3]. Recombinant hBD-1 and its mutants were used in its linearized form for bactericidal testing, nuclear magnetic resonance spectroscopy as well as generation of speci c polyclonal antibodies. Here we present a step-by-step protocol, with minor modi cations, which might be applied also for production of other cysteine-rich and linearized antimicrobial peptides in _E.coli_ and their speci c polyclonal antibodies.

Science, 1999

References and Notes 1. A. Kumar, HA Biebuyck, NL Abbott, GM White- sides, J. Am. Chem. Soc. 114,... more References and Notes 1. A. Kumar, HA Biebuyck, NL Abbott, GM White- sides, J. Am. Chem. Soc. 114, 9188 (1992). 2. DW Wang, SG Thomas, KL Wang, Y. Xia, GM Whitesides, Appl. Phys. Lett. 70, 1593 (1997). 3. RJ Jackman, JL Wilbur, GM ...

Die Erfindung betrifft Proteine, die antibiotisch wirksam sind. Es handelt sich um SAP-2 und SAP-... more Die Erfindung betrifft Proteine, die antibiotisch wirksam sind. Es handelt sich um SAP-2 und SAP-3. Weiterhin umfasst die Erfindung ein Verfahren zur Reinigung von bestimmten antimikrobiellen Proteinen. Daruber hinaus bezieht sich die Erfindung auf eine Verwendung der antimikrobiellen Proteine zur antibiotischen Behandlung oder auf eine Verwendung von Zellen, welche mit einer DNA transfiziert wurden, die fur die erfindungsgemassen Proteine kodiert.

Proceedings of the National Academy of Sciences, 2015

Significance Fungi increasingly cause serious medical problems in immunocompromised populations. ... more Significance Fungi increasingly cause serious medical problems in immunocompromised populations. Antimicrobial peptides are primary effector molecules of innate immune systems. Antimicrobial peptides successfully protect healthy humans from bacterial infections. However, it is largely unknown how and why human body surfaces resist fungal infections. We identified the common epithelial protein, psoriasin (S100A7), in its disulphide-reduced form (redS100A7) as the principal antifungal factor of human body surfaces. redS100A7 kills several pathogenic fungi using a mechanism that differs from conventional antifungal agents. Thus, this study might contribute to a better understanding of human defense systems against fungal infection and the development of urgently needed novel antifungal therapeutics.

PLoS ONE, 2013

Chemerin, a chemoattractant ligand for chemokine-like receptor 1 (CMKLR1) is predicted to share s... more Chemerin, a chemoattractant ligand for chemokine-like receptor 1 (CMKLR1) is predicted to share similar tertiary structure with antibacterial cathelicidins. Recombinant chemerin has antimicrobial activity. Here we show that endogenous chemerin is abundant in human epidermis, and that inhibition of bacteria growth by exudates from organ cultures of primary human skin keratinocytes is largely chemerin-dependent. Using a panel of overlapping chemerin-derived synthetic peptides, we demonstrate that the antibacterial activity of chemerin is primarily mediated by Val 66-Pro 85 , which causes direct bacterial lysis. Therefore, chemerin is an antimicrobial agent in human skin.

Experimental Dermatology, 2006

Journal of Investigative Dermatology, 2008

Human epidermis elaborates two small cationic, highly hydrophobic antimicrobial peptides (AMP), b... more Human epidermis elaborates two small cationic, highly hydrophobic antimicrobial peptides (AMP), beta-defensin 2 (hBD2), and the carboxypeptide cleavage product of human cathelicidin (hCAP18), LL-37, which are co-packaged along with lipids within epidermal lamellar bodies (LBs) before their secretion. Because of their colocalization, we hypothesized that AMP and barrier lipid production could be coregulated by altered permeability barrier requirements. mRNA and immunostainable protein levels for mBD3 and cathelin-related antimicrobial peptide (CRAMP) (murine homologues of hBD2 and LL-37, respectively) increase 1-8 hours after acute permeability barrier disruption and normalize by 24 hours, kinetics that mirror the lipid metabolic response to permeability barrier disruption. Artificial permeability barrier restoration, which inhibits the lipid-synthetic response leading to barrier recovery, blocks the increase in AMP mRNA/protein expression, further evidence that AMP expression is linked to permeability barrier function. Conversely, LB-derived AMPs are also important for permeability barrier homeostasis. Despite an apparent increase in mBD3 protein, CRAMP-/- mice delayed permeability barrier recovery, attributable to defective LB contents and abnormalities in the structure of the lamellar membranes that regulate permeability barrier function. These studies demonstrate that (1) the permeability and antimicrobial barriers are coordinately regulated by permeability barrier requirements and (2) CRAMP is required for permeability barrier homeostasis.

Nature, Jan 26, 1997

... Biochem. Biophys. Res. Comm. 225, 1045–1051 (1996). NATURE | VOL 387 | 26 JUNE 1997 861 A pep... more ... Biochem. Biophys. Res. Comm. 225, 1045–1051 (1996). NATURE | VOL 387 | 26 JUNE 1997 861 A peptide antibiotic from human skin scientific correspondence ...

Nature Immunology, 2005

Human healthy skin is continuously exposed to bacteria, but is particularly resistant to the comm... more Human healthy skin is continuously exposed to bacteria, but is particularly resistant to the common gut bacterium Escherichia coli. We show here that keratinocytes secrete, as the main E. coli-killing compound, the S100 protein psoriasin in vitro and in vivo in a site-dependent way. In vivo treatment of human skin with antibodies to psoriasin inhibited its E. coli-killing properties. Psoriasin was induced in keratinocytes in vitro and in vivo by E. coli, indicating that its focal expression in skin may derive from local microbial induction. Zn(2+)-saturated psoriasin showed diminished antimicrobial activity, suggesting that Zn(2+) sequestration could be a possible antimicrobial mechanism. Thus, psoriasin may be key to the resistance of skin against E. coli.

Journal of Investigative Dermatology, 1992

Neutrophil accumulation in the epidermis is a histologic characteristic of psoriasis. We addresse... more Neutrophil accumulation in the epidermis is a histologic characteristic of psoriasis. We addressed the question: What is the major protein-like chemotactic principle responsible for neutrophil accumulation? Purification of proteinaceous neutrophil chemoattractants from extracts obtained from psoriatic scales by multistep high-performance liquid chromatography (HPLC) yielded three biochemically distinct polypeptides with potent neutrophil chemotactic activity. Aminoterminal amino acid sequence analysis of the quantitatively major neutrophil attractant revealed the sequence ELRXQXIKTYSK, which is identical to that of a 69 residue form of neutrophil-activating peptide-1/interleukin 8 (NAP-1/IL-8). The second major attractant showed the sequence XXVATELRXQXL . . ., which is identical to that of the gene product of the oncogene &quot;gro&quot; as well as &quot;melanoma growth stimulatory activity, MGSA,&quot; whereas the third and minor neutrophil chemotaxin has an NH2-terminal sequence identical with NAP-1/IL-8. Estimation of NAP-1/IL-8-related proteins and gro/MGSA by HPLC combined with bioassay revealed a mean of 3.3 +/- 1.7 ng NAP-1/IL-8-related proteins (n = 11) and 3.2 +/- 1.9 ng gro/MGSA (n = 11) per 1 mg psoriatic scales. In normal heel callus (n = 8), these neutrophil attractants were found at concentrations below 0.02 +/- 0.01 ng/mg. The finding of more than 150-times increased amounts of both NAP-1/IL-8 and gro/MGSA in lesional psoriasis material suggest that these mitogenic as well as neutrophil- and lymphocyte-chemotactic compounds may play an important role in the pathogenesis of psoriasis.

Journal of Investigative Dermatology, 1991

Neutrophil-activating protein-1/interleukin 8 (NAP-1/IL-8), purified to homogeneity from lipopoly... more Neutrophil-activating protein-1/interleukin 8 (NAP-1/IL-8), purified to homogeneity from lipopolysaccharide-stimulated human peripheral blood monocytes, was injected intracutaneously into human skin. Sequential biopsy specimens were taken in order to investigate the sequence of ultrastructural changes induced by the cytokine. Whereas intracutaneous injection of 100 ng of NAP-1/IL-8 per site caused no macroscopic changes, by histology infiltration with polymorphonuclear leukocytes (PMN) and monocytes was present within 1 h and increased at 3 and 5 h. No lymphocyte infiltration was noted. The first ultrastructural changes (30 min) consisted of the presence of cytoplasmic 7-nm microfilament bundles, as well as numerous protrusions of the luminal plasma membrane of endothelial cells (EC). As a striking feature, multiple 100- to 160-nm electron lucent vesicles could be observed in the EC cytoplasm. These structures differed from plasmalemmal vesicles and suggest secretory activity. When PMN and monocytes appeared in the vascular lumen (1 h and later), the number of 100-160-nm electron-lucent vesicles had decreased significantly. In contrast to C5a-injected skin sites, mast cell degranulation was absent.

Journal of Investigative Dermatology, 1996

Epidermal infiltration by polymorphonuclear cells is a prominent feature in psoriatic lesions. Ex... more Epidermal infiltration by polymorphonuclear cells is a prominent feature in psoriatic lesions. Expression of neutrophil-specific chemoattractants by lesional keratinocytes could play an important role in the regulation of this infiltration process. We therefore examined the mRNA expression of GRO-α, a well-characterized peptide with neutrophil-specific activation profile in psoriatic lesions by in situ hybridization. Clusters of clearly detectable and in some