Castleman's Disease, Interleukin 6, and Dehydroepiandrosterone (DHEA)

Copyright 2018, James Michael Howard, Fayetteville, Arkansas, U.S.A.

"Recently "Castleman's disease" caught my attention; I subsequently decided to see if DHEA levels are involved in it.

The connection that attracted my attention was the connection of interleukin-6 (IL-6) with Castleman's disease.

Here is one of the latest citations regarding this combination:

"The Role of Interleukin-6 in Castleman Disease, " (Hematol Oncol Clin North Am. 2018 Feb;32(1):23-36)

"Since its discovery, improvements in treating Castleman disease and its variants have centered on interleukin-6 (IL-6). IL-6 was discovered from T-cell factors (BCDF or BSF-2), which induced B-cell maturation. Most symptoms of the plasma cell variant of Castleman disease are linked to the hyperfunction of IL-6, constitutively produced in the affected lymph nodes (1989), suggesting IL-6 is key in the pathogenesis of multicentric Castleman disease (MCD). The results of several studies have shown that most MCD symptoms and abnormal laboratory results are improved by anti-IL-6 MCD treatments, such as tocilizumab, a humanized anti-IL-6 receptor antibody, and siltuximab, an anti-IL-6 antibody." ...IL-6 is involved and anti-IL-6 activity improves MCD.

It is known that DHEA reduces IL-6.

"Serum Dehydroepiandrosterone (DHEA) and DHEA Sulfate Are Negatively Correlated with Serum Interleukin-6 (IL-6), and DHEA Inhibits IL-6 Secretion from Mononuclear Cells in Man in Vitro: Possible Link between Endocrinosenescence and Immunosenescence, (The Journal of Clinical Endocrinology & Metabolism, Volume 83, Issue 6, 1 June 1998, Pages 2012–2017)

"In summary, the data indicate a functional link between DHEA or ASD and IL-6. It is concluded that the increase in IL-6 production during the process of aging might be due to diminished DHEA and ASD [androstenedione] secretion. Immunosenescence may be directly related to endocrinosenescence, which, in turn, may be a significant cofactor for the manifestation of inflammatory and age-related diseases." (Androstenedione is a precursor of DHEA.)

It is my hypothesis that evolution selected dehydroepiandrosterone (DHEA) because it optimizes replication and transcription of DNA, that is, genes. Therefore, DHEA levels affect all tissues and all tissues compete for available DHEA, especially the brain. (I think evolutionary selection of DHEA produced Mammalian. "Hormones in Mammalian Evolution," Rivista di Biologia / Biology Forum 2001; 94: 177-184, ). DHEA naturally begins to decline around the ages of twenty to twenty-five, reaching very low levels in old age. When DHEA is low or decreasing, all tissues are adversely affected; when DHEA is too low, death occurs.

Castleman's syndrome can occur at any age but increases around ages 20-30 and "is most common in 40-60 year olds." These correspond with the natural initial decline of DHEA and its subsequent decline in old age. DHEA is known to decline in HIV / AIDS. "MCD occurring in HIV patients has been associated with a poor prognosis." (Proc (Bayl Univ Med Cent). 2014 Jan; 27(1): 28–30).

I submit low DHEA is directly involved in the etiology of Castleman's disease and the increased interleukin-6 connected with the disease. Increased IL-6 is simply an identifiable consequence of reduced DHEA. As I stated, above, reduced DHEA causes adverse consequences in all tissues. That is, in a normal genome, all gene activity would decline; old age. However, as I have suggested elsewhere, the loss of DHEA will expose less than optimally functional genes in other disease such as Alzheimer's disease, etc. When this exposes genes when DHEA begins to decline / continues from the natural decline this is "early onset;" when the decline of old age occurs, genes will decline in competition with others, sometimes genes involved in these disease which is characteristic, also, of diseases like AD which is "late onset."

I submit there is a less than optimally functioning gene in Castleman's disease produces its symptoms based on DHEA levels.