Regulation of IL-1 receptor antagonist by TSH in fibrocytes and orbital fibroblasts.
BACKGROUND
The IL-1 family plays important roles in normal physiology and mediates inflammation. The actions of IL-1 are modulated by multiple IL-1 receptor antagonists (IL-1RA), including intracellular and secreted forms. IL-1 has been implicated in autoimmunity, such as that occurring in Graves' disease (GD) and its inflammatory orbital manifestation, thyroid-associated ophthalmopathy (TAO). We have previously reported that CD34(+) fibrocytes, monocyte-lineage bone marrow-derived cells, express functional TSH receptor, the central antigen in GD. When activated by TSH, they produce IL-6, IL-8, and TNF-α. Moreover, they infiltrate the orbit in TAO in which they transition into CD34(+) fibroblasts and comprise a population of orbital fibroblasts (OFs). Little is known currently about any relationship between TSH, TSH receptor, and the IL-1 pathway.


OBJECTIVE
The objective of the study was to determine whether TSH regulates IL-1RA in fibrocytes and OFs.


METHODS
Fibrocytes and OFs were collected and analyzed from healthy individuals and those with GD in an academic clinical practice.


METHODS
Real-time PCR, Western blot analysis, reporter gene assays, and cell transfections were performed.


RESULTS
TSH induces the expression of IL-1RA in fibrocytes and GD-OFs. The patterns of induction diverge quantitatively and qualitatively in the two cell types. This results from relatively small effects on gene transcription-related events but a greater influence on secreted IL-1RA and intracellular IL-1RA mRNA stabilities. These actions of TSH are dependent on the intermediate induction of IL-1α and IL-1β.


CONCLUSIONS
Our findings for the first time directly link activities of the TSH and IL-1 pathways. Furthermore, they identify novel molecular interactions that could be targeted as therapy for TAO.
Department of Ophthalmology and Visual Sciences (B.L., T.J.S.) and Department of Internal Medicine (T.J.S.), Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan 48105.
Bin
B
Li
Terry J
TJ
Smith
D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D049970:Graves Ophthalmopathy / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics* / Q000378:metabolism; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D009915:Orbit / Q000166:cytology* / Q000378:metabolism*; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D020871:RNA Stability / Q000187:drug effects; D013972:Thyrotropin / Q000494:pharmacology* / Q000502:physiology
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D013972:Thyrotropin