Linkage of IL-6 with neutrophil chemoattractant expression in virus-induced ocular inflammation.
OBJECTIVE
Herpes simplex virus (HSV)-1 infection of the murine cornea is known to stimulate a vigorous interleukin (IL)-6 response, but whether this pleiotropic cytokine is an essential participant in corneal inflammation is unclear. This study was designed to compare the early inflammatory response in IL-6 gene-deficient mice to that in wild-type hosts.


METHODS
Gene knockout and wild-type mice (C57BL/6 background) were infected intracorneally with HSV-1 (strain RE) and observed through clinical examination and immunohistochemistry for the development of corneal opacity. Virus corneal titers were determined by standard plaque assay on Vero cells. Cytokine and chemokine levels in corneal lysates were measured with commercial ELISA kits.


RESULTS
Corneal opacity in IL-6(-/-) mice was substantially diminished in comparison with IL-6(+/+) hosts 24 to 48 hours after intracorneal viral infection, and corneal levels of (MIP)-2 and MIP-1alpha were significantly reduced. Local administration of IL-6 at the time of infection restored corneal opacity and chemokine levels to that of wild-type hosts. Antibody neutralization of endogenous IL-6 in IL-6(+/+) animals reduced corneal opacity scores and MIP-2 levels to that of IL-6(-/-) mice. Ex vivo studies with excised corneal buttons revealed that uninfected IL-6(-/-) corneas injected with IL-6 produced MIP-2 and MIP-1alpha at levels comparable to that seen in IL-6(+/+) hosts.


CONCLUSIONS
Collectively, these results suggest that IL-6 promotes corneal inflammation by acting in an autocrine-paracrine fashion to induce resident corneal cells to make MIP-2 and MIP-1alpha, which in turn recruit neutrophils to the virus infection site.
Fenton
Robin R
RR
Department of Microbiology and Immunology, School of Medicine, University of South Alabama, 307 University, Mobile, AL 36688, USA.
Molesworth-Kenyon
Sara
S
Oakes
John E
JE
Lausch
Robert N
RN
D000818:Animals; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism*; D003315:Cornea / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D003318:Corneal Opacity / Q000378:metabolism / Q000473:pathology / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay; D018259:Herpesvirus 1, Human / Q000502:physiology*; D007124:Immunoenzyme Techniques; D015850:Interleukin-6 / Q000502:physiology*; D016849:Keratitis, Herpetic / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology*
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D015850:Interleukin-6; D019402:Macrophage Inflammatory Proteins