Role of proinflammatory cytokines in the impaired lacrimation associated with autoimmune xerophthalmia.
OBJECTIVE
To determine the effects of the proinflammatory cytokines interleukin (IL)-1alpha, IL-1beta, and tumor necrosis factor (TNF)-alpha on neurally mediated lacrimal gland protein secretion and to determine whether the amount of IL-1beta protein is upregulated in inflamed lacrimal glands of the MRL/lpr mouse, a murine model of human Sjögren syndrome.


METHODS
Lacrimal gland lobules of BALB/c mice were prepared and incubated for 2 hours in the presence or absence of recombinant human (rh)IL-1alpha, rhIL-1beta (10 ng/mL each), or rhTNFalpha (50 ng/mL). Peroxidase secretion in response to depolarizing KCl (75 mM) solution was measured by spectrofluorometric assay. In another set of experiments, saline, rhIL-1beta (1 microg), or an antibody against IL-1 receptor type I (IL-1RI), with or without rhIL-1beta, was injected (2 microL) into the lacrimal glands of anesthetized BALB/c mice. Twenty-four hours later, lacrimal gland lobules were prepared and peroxidase secretion was measured. The amount of IL-1beta protein in lacrimal gland acinar cell lysates prepared from 3-, 9-, and 13-week-old BALB/c, MRL/(+), and MRL/lpr mice was determined by ELISA.


RESULTS
KCl-induced peroxidase secretion was inhibited in vitro 62%, 66%, and 53% by rhIL-1alpha, rhIL-1beta, and rhTNFalpha, respectively. In vivo, rhIL-1beta inhibited KCl-induced peroxidase secretion by 72%. This inhibitory effect of IL-1beta was completely reversed by an antibody against IL-1RI. Compared with 3-week-old mice, the amount of IL-1beta protein was upregulated 15- and 21-fold in lacrimal gland acinar cells isolated from 9- and 13-week-old MRL/lpr mice, respectively.


CONCLUSIONS
Proinflammatory cytokines inhibit neurally mediated lacrimal gland secretion. The amount of IL-1beta protein is upregulated in acinar cells prepared from lacrimal glands infiltrated with lymphocytes. These results suggest that elevated levels of IL-1beta, as they occur in Sjögren syndrome exocrine glands, may impair the secretory function of these tissues.
Zoukhri
Driss
D
Department of Ophthalmology, Schepens Eye Research Institute, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA. zoukhri@vision.eri.harvard.edu
Hodges
Robin R
RR
Byon
Dosek
D
Kublin
Claire Larkin
CL
D000367:Age Factors; D000818:Animals; D001327:Autoimmune Diseases / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology*; D007765:Lacrimal Apparatus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D009195:Peroxidase / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011994:Recombinant Proteins; D013050:Spectrometry, Fluorescence; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation; D014985:Xerophthalmia / Q000378:metabolism* / Q000473:pathology
D007375:Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D011189:Potassium Chloride; D009195:Peroxidase