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Cathelicidin Antimicrobial Peptides Inhibit Hyaluronan-Induced Cytokine Release and Modulate Chronic Allergic Dermatitis¹

Yasuhide Morioka^*,, Kenshi Yamasaki^*, Donald Leung and Richard L. Gallo^2,*

^* Division of Dermatology, University of California, San Diego, and Veterans Affairs San Diego Health Care System, San Diego, California 92161; Discovery Research Laboratories, Shionogi and Company, Osaka, Japan; and Division of Allergy and Immunology, Department of Pediatrics, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver, Colorado 80206

Antimicrobial peptides such as cathelicidins can modulate inflammation by interfering with TLR function. Small fragment hyaluronan (HA) is released following injury, and is an endogenous ligand for TLR4 as well as CD44. In this study, we examined the interactions of cathelicidin with HA. Cathelicidin inhibited HA induced MIP-2 release from mouse bone marrow derived macrophages in a CD44 dependent manner but did not inhibit MALP2-induced MIP-2 release. This inhibitory activity was more potent than that of a peptide inhibitor of HA binding (Pep-1) and independent of Gi protein coupled or EGF-R signaling, both targets of cathelicidin inhibited HA-induced MIP-2 release. In assay of cell binding to HA, cathelicidins also significantly inhibited this process, suggesting that this antimicrobial peptide can interfere in other membrane binding events mediated by HA. The significance of this inhibition was demonstrated in a skin inflammation model induced by repeated application of 2,4-dinitrofluorobenzene. This induced an increase in HA at the site of application and was partially CD44 dependent. Camp^–/– mice lacking cathelcidin demonstrated a large increase in ear swelling, cell infiltration, and MIP-2 expression compared with wild type mice. These results suggest that cathelicidin has anti-inflammatory activity in skin that may be mediated in part by inhibition of HA-mediated processes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants NIH R01AR052728, NIH R01 AI052453, and a Veterans Affairs Merit Award (to R.L.G.) and NIH AR41256 (to D.L.).

² Address correspondence and reprint requests to Dr. Richard L. Gallo, Division of Dermatology, University of California, San Diego, Veterans Affairs San Diego Health Care System, San Diego, 9111B, 3350 La Jolla Village Drive, San Diego, California 92161. E-mail address: rgallo{at}ucsd.edu

³ Abbreviations used in this paper: AMP, antimicrobial peptide; AD, atopic dermatitis; WT, wild type; DC, dendritic cell; HA, hyaluronan; M-CSF, macrophage-CSF; PTX, pertussis toxin; EGFR, epidermal growth factor receptor; DNFB, 2,4-dinitrofluorobenzene; mCRAMP, mouse cathelicidin-related antimicrobial peptide; BMDM, bone marrow derived macrophage; NHEK, normal human epidermal keratinocyte; PMNs, polymorphonuclear leukocyte; MALP-2, macrophage-activating lipopeptide of 2-kDa molecular mass.