Abstract: ACTH is the major regulator of the body's adaptive response to stress and the physiological stimulus for glucocorticoid secretion. A hypothalamic corticotropin release inhibiting factor (CRIF) that inhibits ACTH synthesis and secretion has long been postulated but was not characterized until recently. We have recently identified a 22 amino acid peptide, prepro-thyrotropin releasing hormone (TRH) 178-199 that inhibits basal and stimulated ACTH synthesis and secretion in vitro and stress-induced ACTH secretion in vivo. Prepro-TRH 178-199 is abundant in several brain regions, including the external zone of the median eminence, where its concentration changes in response to stress. We propose that this peptide is a physiological regulator of ACTH production: an endogenous CRIF. Because prepro-TRH 178-199 is encoded within the same precursor as TRH, its expression is likely to be negatively regulated by thyroid hormones leading to changes in endogenous glucocorticoid levels. Streptococcal cell wall (SCW)-induced inflammation, a model of rheumatoid arthritis (RA), was alleviated after long-term thyroxine treatment. Inversely, a hypothyroid milieu led to decreased basal hypothalamic-pituitary-adrenal activity, but increased expression of IL-1β and MIP-1α, specific markers for RA in humans. These results suggest that this putative CRIF may be an important component in the development of RA and that regulation of preproTRH may be highly relevant to the development of other autoimmune diseases that are also exacerbated by low endogenous glucocorticoid levels.