Influence of a Co-stimulation of Human Leucocytes with an Escherichia coli Preparation and Fixed Immunoglobulins on Cytokine Release in the Presence of Hydrocortisone

Abstract

Pharmaceuticals of biological origin consisting of bacterial culture suspensions (BCS) as active ingredients have long been used for the treatment of hemorrhoidal diseases and chronic anal pruritogenic eczemas. However, some of these pharmaceuticals often contain glucocorticoids such as hydrocortisone as an anti-inflammatory supplement. Therefore, the question arises whether the claimed immunostimulatory capacity of the bacterial culture suspension might be altered by the steroid. Up to now, numerous reports support the evidence that the stimulation of the different Fc-receptor subtypes on leucocytes result in profound immunoregulatory activities influencing phagocytosis and antigen processing, antibody-dependent cytotoxicity or secretory functions thereby enhancing the overall activities of the immune system towards foreign antigens/pathogens. With these findings in mind it was investigated whether the immunomodulatory capacity(s) of the BCS in the presence of hydrocortisone will be modified by solid-phase bound immunoglobulins (Igs). For this purpose freshly prepared human peripheral blood leucocytes (PBLs) were incubated with different concentrations of the BCS (0.1, 1, 10 micrograms/ml), either with or without fixed human immunoglobulins in the presence of increasing concentrations of hydrocortisone. As a parameter of PBL activation the secretion of different cytokines was measured, e.g. tumor necrosis factor alpha (TNF-alpha), interleukin-10 (IL-10) and granulocyte-macrophage colony stimulating factor (GM-CSF). Cytokines were determined with specific sandwich ELISAs. With this modified cell culture system it was demonstrated that the immunosuppressive activities, normally caused by hydrocortisone, were partially antagonized by the combination of BCS plus fixed Igs. TNF-alpha and GM-CSF were significantly more produced, even in the presence of hydrocortisone, whereas the synthesis of IL-10 was diminished by fixed Igs. However, this effect could be reversed with increasing concentrations of hydrocortisone. These results raise the possibility that in the natural environment, e.g. the rectal mucosa, antigens derived from the BCS are bound by specific Igs, thereby modifying secretory and effector functions of locally present leucocytes in another way as free antigens. The biological relevance of these in vitro data with respect to the therapeutic benefit of the BCS preparations with hydrocortisone will be discussed considering recent findings in the literature.

Exogenous and endogenous glucocorticoids in rheumatic diseases

“…Another study used freshly prepared human peripheral blood leukocytes incubated with bacterial culture suspensions, either with or without fixed human immunoglobulins, in the presence of increasing concentrations of cortisol (55). The immunosuppressive activities normally caused by cortisol were partially antagonized, leading to increased TNF and granulocyte–macrophage colony‐stimulating factor secretion, whereas the expression of IL‐10 was diminished.…”

“…The immunosuppressive activities normally caused by cortisol were partially antagonized, leading to increased TNF and granulocyte–macrophage colony‐stimulating factor secretion, whereas the expression of IL‐10 was diminished. However, this effect could be reversed with increasing concentrations of cortisol (55), which indicates that the concentration of glucocorticoids plays an important role. Indeed, a recent study showed that low levels of corticosterone enhanced the nitric oxide production as well as messenger RNA expression of the proinflammatory cytokines, chemokines, and enzymes required for mediator synthesis (56), while high levels of corticosterone strongly repressed macrophage function; these effects were mediated by the classic GR.…”

Experience of using an individual approach in the anal fissures treatment

“…Отметим, что в России таковыми препаратами для местного применения, относящимися по международной анатомической терапевтически химической классификации к группе иммуномодуляторов, являются мази и свечи Постеризан и Постеризан форте, отличающийся наличием в комбинированном препарате топических дозировок гидрокортизона. Известно, что инактивированные штаммы и эндотоксины E. coli усиливают эффект Т-клеточной активации, хотя не являются прямым индуктором антигенспецифической активации [12,13] (рис. 1).…”

“…Сопутствующее фагоцитозу появление медиаторов (таких, как кислородные радикалы) вносит вклад в эффективное и успешное удаление болезнетворных микроорганизмов. Несмотря на осторожное отношение специалистов хирургического профиля к иммуномодуляторам, клинические исследования показывают значительные терапевтические эффекты местного применения препаратов на базе инактивированных фенолом штаммов E. coli (особенно Постеризана форте) при лечении воспалительной аноректальной патологии [12,13].…”

“…Возросшая надежность и эффективность методов оперативного лечения анальных трещин неоднократно подтверждались статистически обоснованными данными многоцентровых исследований, тем не менее остается стабильным и не имеет тенденции к снижению процент неудовлетворительных исходов [2,3,12]. Более того, повсеместное внедрение сфинктеротомии резко увеличило число осложнений и неудовлетворительных исходов лечения, связанных с нарушением функции удержания кала и газов [5,6,8].…”