A central nervous system defect in biosynthesis of corticotropin-releasing hormone is associated with susceptibility to streptococcal cell wall-induced arthritis in Lewis rats.

Abstract

We have recently found that susceptibility to streptococcal cell wall (SCW)-induced arthritis in Lewis (LEW/N) rats is due, in part, to defective inflammatory and stress mediator-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Conversely, the relative arthritis resistance of histocompatible Fischer (F344/N) rats is related to their intact responses to the same stimuli. Specifically, LEW/N rats, in contrast to F344/N rats, have markedly impaired plasma corticotropin and corticosterone responses to SCW, recombinant human interleukin lat, the serotonin agonist quipazine, or synthetic rat/human corticotropin-releasing hormone (CRH). To explore the mechanism of this defect, we examined the functional integrity of the hypothalamic CRH neuron in LEW/N rats compared to F344/N rats. LEW/N rats, in contrast to F344/N rats, showed profoundly deficient paraventricular nucleus CRH mRNA levels and hypothalamic CRH content in response to SCW. Compared to F344/N rats, there was no increase in LEW/N hypothalamic CRH content or CRH release from explanted LEW/N hypothalami in organ culture in response to recombinant interleukin ar. These data provide strong evidence that the defective LEW/N corticotropin and corticosterone responses to inflammatory and other stress mediators, and the LEW/N susceptibility to experimental arthritis, are due in part to a hypothalamic defect in the synthesis and secretion of CRH. The additional finding of deficient expression in LEW/N rats of the hypothalamic enkephalin gene, which is coordinately regulated with the CRH gene in response to stress, suggests that the primary defect is not in the CRH gene but is instead related to its inappropriate regulation.Inbred Lewis (LEW/N) female rats develop severe proliferative and erosive arthritis, which mimics human rheumatoid arthritis, in response to a single intraperitoneal injection of group A streptococcal cell wall peptidoglycan group-specific polysaccharide (SCW). Histocompatible Fischer (F344/N) rats, on the other hand, do not develop arthritis in response to the same SCW stimulus (1-8). We previously found that the susceptibility of LEW/N rats to SCW arthritis is related to their defective hypothalamic-pituitary-adrenal (HPA) axis responses to inflammatory and other stress mediators and that the relative SCW arthritis resistance of F344/N rats is related to their intact HPA responses to the same stimuli (9).Specifically, LEW/N rats, in contrast to F344/N rats, have markedly impaired plasma corticotropin (ACTH) and corticosterone responses to intraperitoneally injected SCW, to recombinant human interleukin la (rIL-la), to the serotonin agonist quipazine, and to synthetic rat/human corticotropinreleasing hormone (CRH). In addition, LEW/N rats, compared to F344/N rats, have smaller adrenal glands and larger thymuses, consistent with chronic lack of stimulation by ACTH and suppression by corticosterone, respectively (9). Furthermore, arthritis and severe inflammation can be induced in otherwise SCW arthritis-resistant F344/N ...

Increased cortisol relative to adrenocorticotropic hormone predicts improvement during anti–tumor necrosis factor therapy in rheumatoid arthritis

“…The findings of this study position the HPA axis, particularly the adrenal glands, centrally in RA pathophysiology. Thus, our findings confirm the central role of the HPA axis in RA as studied in a rat model of arthritis (2).…”

“…In an animal model of arthritis, seminal work at the beginning of the 1990s has positioned the hypothalamic-pituitary-adrenal (HPA) axis centrally in chronic inflammation (2). However, findings of those studies have never been confirmed in patients with RA.…”

Individual Behavioral Characteristics of Wild-Type Rats Predict Susceptibility to Experimental Autoimmune Encephalomyelitis

“…Lewis rats are highly susceptible to SCW arthritis and other autoimmune models, whereas Fischer rats are resistant. Investigation of the neuroendocrine reactivity in these two strains of rats demonstrated that the reactivity of the hypothalamo-pituitary-adrenal axis in Lewis rats is lower than in Fischer rats (Sternberg, Young, Bernardini, Calogero, Chrousos, Gold, & Wilder, 1989b;Sternberg et al, 1989a). These differences in reactivity were observed after activation of the HPA axis by immune stimuli, e.g., injection with SCW or LPS, as well as after exposure to a novel environment (Sternberg et al, 1989a).…”

Corticotropin-releasing hormone (Crh) maps to mouse Chromosome 3

“…Animal studies suggest that other consequences of CRH deficiency are possible. For example, impaired synthesis and secretion of CRH in the paraventricular nucleus of the hypothalamus of the Lewis (LEW/N) rat leads to an increased susceptibility to streptococcal cell wall-induced arthritis (Sternberg et al 1989). The expression of CRH in multiple regions of the mouse brain and in some peripheral tissues beginning at embryonic day 13.5 suggests that CRH expression may also play an important role in development (C. Keegan, unpublished data).…”